Psoriasis treatment

ABSTRACT

The present invention relates to the use of renin inhibitors and to renin inhibitor compositions for treatment of psoriasis.

This is a continuation-in-part of U.S. Pat. application Ser. No.678,111, filed Apr. 4, 1991, now abandoned which is acontinuation-in-part of U.S. Pat. application Ser. No. 513,367, filedApr. 23, 1990.

TECHNICAL FIELD

The present invention relates to the use of renin inhibitors and torenin inhibitor compositions for treatment of psoriasis.

BACKGROUND ART

Psoriasis is a chronic skin disease which is known to be difficult totreat. Psoriasis is characterized by discrete and confluent, reddish,silvery-scaled maculopapules. These psoriatic lesions occur most oftenon the elbows, knees, trunk and scalp. Current treatment for psoriasisinclude the use of agents such as anthralin (dihydroxyanthralin),azarabine, colchicine, fluorouracil, methotrexate, methoxsalen(8-methoxypsoralen), resorcinol, retinoids (for example, retinoic acid),corticosteroids (for example, clobetasol propionate, trimcinoloneacetonide and the like), cyclosporin, iodochlorhydroxyquin, salicyclicacid, vitamin D, dapsone, somatostatin, sulfur, tars and zinc oxide.Ultra-violet light treatment, alone or in combination with other agentssuch as psoralen (i.e., PUVA treatment), is also used to treatpsoriasis.

There are reports that the activity of the renin-angiotensin-aldosteronesystem is enhanced in patients with psoriasis (Ena, et al., ActaCardiologica XL 199 (1985); Ryder, et al., Clin. Chem. Acta 153 143(1985)). However, there is no established cause and effect relationshipbetween the renin-angiotensin-aldosterone system and psoriasis.

Renin is a proteolytic enzyme synthesized and stored principally in thespecific part of the kidney called the juxtaglomerular apparatus.Inhibitors of renin have been disclosed as agents for the treatment ofhypertension, congestive heart failure and glaucoma.

DISCLOSURE OF THE INVENTION

It has now been discovered that renin inhibitors are useful for thetreatment of psoriasis.

Examples of renin inhibitors and the methods for preparing the renininhibitors include, but are not limited to, those disclosed in thefollowing references, which are hereby incorporated by reference.

REFERENCE DISCLOSING RENIN INHIBITORS COMPOUNDS

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Preferred renin inhibitors and methods for making them include thosedisclosed in U.S. Pat. No. 4,826,815, issued May 2, 1989; U.S. Pat. No.4,857,507, issued Aug. 15, 1989; U.S. Pat. No. 4,826,958, issued May 2,1989; U.S. Pat. No. 4,837,204, issued Jun. 6, 1989; U.S. Pat. No.4,845,079 issued Jul. 4, 1989, all of which are hereby incorporated byreference. Preferred renin inhibitors and methods for making them alsoinclude those disclosed in copending U.S. Pat. applications, U.S. Ser.No. 403,906, filed Sept. 1, 1989; U.S. Ser. No. 231,869, filed Aug. 16,1988 (EP0307837, published Mar. 22, 1989); U.S. Ser. No. 132,356, filedDec. 18, 1987 (WO88/05050, published Jul. 14, 1988); PCT/US89/04385,filed Oct. 3, 1989 (WO90/03971, published Apr. 19, 1990);PCT/US89/04649, filed Oct. 18, 1989 (WO90/04917, published May 17,1990); and U.S. Ser. No. 564,925, filed Aug. 9, 1990 all of which arehereby incorporated by reference.

The preferred renin inhibiting compounds of this invention are selectedform the group consisting of compounds of the formula: ##STR1## whereinA is hydrogen, loweralkyl, arylalkyl, --OR₂₀ wherein R₂₀ is hydrogen, orloweralkyl, --NR₂₁ R₂₂

wherein R₂₁ and R₂₂ are independently selected from hydrogen andloweralkyl;

or A is ##STR2## wherein B is NH, O, CH₂ or NHCH₂ ; and R₂₃ isloweralkyl, alkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino,dialkylamino, carboxyalkyl, alkoxycarbonyalkyl,(dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl,(heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;

W is C═O, CH₂ or CHOH;

U is CH₂ or NR2 wherein R₂ is hydrogen or loweralkyl, provided that whenW is CHOH then U is CH₂ ;

R₁ is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl,(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl,phenethyl, phenoxy, thiophenoxy or anilino; provided that when R₁ isphenoxy, thiophenoxy or anilino, then B is CH₂ or A is hydrogen;

R₃ is loweralkyl, (thioalkoxy)alkyl, benzyl or heterocyclic ringsubstituted methyl;

R₅ is hydrogen or lower alkyl;

R₆ is loweralkyl, cycloalkylmethyl, or benzyl;

R₇, R₈ and R₉ are hydrogen or loweralkyl and may be the same ordifferent;

V is NH, O,S,SO,SO₂ or CH₂ ;

R₁₀ is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyl or anN-protecting group, or V and R₁₀ taken together are N₃ ; with theproviso that R₁₀ may be an N-protecting group only when V is NH;##STR3## wherein A_(b) is hydrogen, loweralkyl, arylalkyl, OR_(20b) orSR_(20b) wherein R_(20b) is hydrogen, loweralkyl or aminoalkyl, NR_(21b)R_(22b) wherein R_(21b) and R_(22b) are independently selected fromhydrogen, loweralkyl, aminoalkyl, cyanalkyl and hydroxyalkyl; or A_(b)is ##STR4## wherein B_(b) is NH, alkylamino, S, O, CH₂ or CHOH; andR_(23b) is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy,hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino,alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino,(dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl,alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,(N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl,or a substituted or unsubstituted heterocyclic;

W_(b) is C═O or CHOH;

U_(b) is CH₂ or NR₂₆ wherein R_(2b) is hydrogen or loweralkyl, providedthat when W_(b) is CHOH then U_(b) is CH₂ ;

R_(1b) is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl,(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl,phenethyl, phenoxy, thiophenoxy or anilino; provided that when R_(1b) isphenoxy, thiophenoxy or anilino, then B_(b) is CH₂ or CHOH or A_(b) ishydrogen;

R_(3b) is loweralkyl, loweralkenyl, benzyl or heterocyclic ringsubstituted methyl;

R_(5b) is hydrogen or loweralkyl;

R_(6b) is loweralkyl, cycloalkylmethyl, or benzyl;

R_(10b) is loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl, arylalkyolor an N-protecting group, or L_(b) and R_(10b) taken together can be N₃,with the proviso that when L_(b) is NH then R_(10b) is an N-protectinggroup;

R_(13b) is CHOH or CO;

R_(14b) is CH₂, CF₂ or CF with the proviso that when R_(13b) is CO thenR_(14b) is CF₂ ;

R_(15b) is CH₂, CHR_(25b) wherein R_(25b) is loweralkyl, cycloalkyl,cycloalkylalkyl, aryl or arylalkyl, or R_(14b) and R_(15b) takentogether can be ##STR5## with the proviso that when R_(14b) is CF₂ thenR_(15b) is CH₂ ;

L_(b) is O,S,SO,SO₂,NR_(26b) wherein R_(26b) is hydrogen or loweralkyl,or NR_(27b) C(O) wherein R_(27b) is hydrogen or loweralkyl; ##STR6##wherein A_(c) is ##STR7## wherein B_(c) is NH, or CH₂ ; and R_(23c) isloweralkyl, alkoxy, or a substituted or unsubstituted heterocyclic;

W_(c) is C═O;

U_(c) is NR_(2c) wherein R_(2c) is hydrogen or loweralkyl;

R_(1c) is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl,(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, orphenethyl;

R_(3c) is loweralkyl, benzyl or heterocyclic ring substituted methyl; p1R_(5c) is hydrogen or loweralkyl;

R_(6c) is loweralkyl, cycloalkylmethyl, benzyl, or CH₂ R_(24c) whereinR_(24c) is selected from 1,3-dioxan-2-yl, 1,3-dioxolan-2-yl,1,3-dithiolan-2-yl and 1,3-dithian-2-yl;

R_(16c) is CH₂, CF₂ or CHR_(63c) where R_(63c) is loweralkyl, hydroxy,hydroxyalkyl, alkoxy, allyl, arylalkoxy or thioalkyl;

R_(17c) is hydrogen or loweralkyl;

R_(18c) is loweralkyl or lipophilic or aromatic amino acid side chain;

D_(c) is hydrogen, loweralkyl or --CH₂ OR_(28c) wherein R_(28c) ishydrogen, loweralkyl or arylalkyl; ##STR8## wherein A_(d) is hydrogen,loweralkyl, arylalkyl, --OR_(20d) or --SR_(20d) wherein R_(20d) ishydrogen, loweralkyl or aminoalkyl, --NR_(21d) R_(22d) wherein R_(21d)and R_(22d) are independently selected from hydrogen, loweralkyl,aminoalkyl, cyanalkyl and hydroxyalkyl; of A_(d) is ##STR9## whereinB_(d) is NH, alkylamino, S, O, CH₂ or NCH₂, and R_(23d) is loweralky,cycloalkyl, aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy,dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl, amino, alkylamino,dialkylamino, (hydroxyalkyl)(alkyl)amino,((dialkylamino)alkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino,aminoalkyl, N-protected aminoalkyl, alkylaminoalkyl, carboxyalkyl,alkoxycarbonylalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl,(heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;

W_(d) is C═O or CHOH;

U_(d) is CH_(d) or NR_(2d) wherein R_(2d) is hydrogen or loweralkyl,provided that when W_(d) is CHOH then U_(d) is CH₂ ;

R_(1d) is CHR_(24d) wherein R_(24d) is loweralkyl, cycloalkylalkyl,benzyl, 4-methoxybenzyl, 4-hydroxybenzyl,halobenzyl,(1-naphthyl)methyl,(2-naphthyl)methyl,(4-imidazoyl)methyl,(alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl, or phenethyl, or R_(1d)is C═CHR_(25d) wherein R_(25d) is aryl;

R_(3d) is loweralkyl, alkenyl, benzyl or heterocyclic ring substitutedmethyl; p1 R_(5d) is hydrogen or loweralkyl;

R_(6d) is loweralkyl, cycloalkylmethyl, or benzyl;

R_(11d) is hydrogen or hydroxy;

n is 0 or 1; when n is 0 then T_(d) is alkylidene or alkylidene oxide;and when n is 1 then Z_(d) is hydrogen or hydroxy and T_(d) isloweralkyl, hydroxyalkyl, aminoalkyl, haloalkyl, or azidoalkyl;

R_(12d) is hydrogen, loweralkyl, cycloalkylalkyl, arylalkyl, aminoalkyl,or dialkylaminoalkyl; ##STR10## wherein A_(e) is hydrogen, loweralkyl,arylalkyl, --OR_(20e) or --SR_(20e) wherein R_(20e) is hydrogen,loweralkyl or aminoalkyl, --NR_(21e) R_(22e) wherein R_(21e) and R_(22e)are independently selected from hydrogen, loweralkyl, aminoalkyl,cyanoalkyl and hydroxyalkyl;

or A_(e) is ##STR11## wherein B_(e) is NH, alkylamino, S, O, CH₂ orCHOH; and R_(23e) is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy,alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl,amino, alkylamino, dialkylamino, (hydroxyalkyl)(alkyl)amino,(dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl,alkylaminoalkyl, carboxyalkyl, alkoxycarbonylalkyl,(N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl, (heterocyclic)alkyl,or a substituted or unsubstituted heterocyclic;

W_(e) is C═O;

U_(e) is NR_(2e) wherein R_(2e) is hydrogen or loweralkyl;

R_(1e) is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl,(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl,phenethyl, phenoxy, thiophenoxy or anilino, provided that when R_(1e) isphenoxy, thiophenoxy or anilino, then B_(e) is CH₂ or CHOH or A_(e) ishydrogen;

R_(3e) is loweralkyl, benzyl or heterocyclic ring substituted methyl;

R_(5e) is hydrogen or loweralkyl;

R_(6e) is loweralkyl, cycloalkylmethyl, or benzyl;

M_(e) is O, NH or S;

R_(10e) is hydrogen, loweralkyl, cycloalkyl, (cycloalkyl)alkyl, aryl,arylalkyl or an N-protecting group; ##STR12## wherein A_(f) is hydrogen,loweralkyl, arylalkyl, --OR_(10f) or --SR_(10f) wherein R_(10f) ishydrogen, loweralkyl or aminoalkyl, --NR_(11f) R_(12f) wherein R_(11f)and R_(12f) are independently selected from hydrogen, loweralkyl,aminoalkyl, cyanoalkyl, hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl,(amino)carboxyalkyl, ((N-protected)amino)carboxyalkyl,(alkylamino)carboxyalkyl, ((N-protected)alkylamino)carboxyalkyl,(dialkylamino)carboxyalkyl, (amino)alkoxycarbonylalkyl,((N-protected)amino)alkoxycarbonyalkyl, (alkyamino)alkoxycarbonylalkyl,((N-protected)alkylamino)alkoxycarbonylalkyl and(dialkylamino)alkoxycarbonylalkyl;

or A_(f) is ##STR13## wherein B_(f) is NH, alkylamino, S, O, CH₂ or CHOHand R_(23f) is loweralkyl, cycloalkyl, aryl, arylalkyl, alkoxy,alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy, arylalkoxy, arylalkoxyalkyl,amino, alkylamino, dialkylamino,(hydroxyalkyl)(alkyl)amino,(dihydroxyalkyl)(alkyl)amino, aminoalkyl,N-protectedaminoalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl,dialkylaminoalkyl, carboxyalkyoxyalkyl, (alkoxycarbonyl)alkoxyalkyl,carboxyalkyl, carboxyalkylamino, alkoxycarbonylalkyl,alkoxycarbonyalkylamino, (amino)carboxyalkyl, (amino)carboxyalkylamino,((N-protected)amino)carboxyalkyl, ((N-protected)amino)carboxyalkylamino,(alkylamino)carboxyalkyl, (alkylamino)carboxyalkylamino,((N-protected)alkylamino)carboxyalkyl,((N-protected)alkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl,(dialkylamino)carboxyalkylamino, (amino)alkoxycarbonyalkyl,(amino)alkoxycarbonylalkylamino,((N-protected)amino)alkoxycarbonylalkyl,((N-protected)amino)alkoxycarbonylalkylamino,(alkylamino)alkoxycarbonylalkyl, (alkylamino)alkoxycarbonylalkylamino,((N-protected)alkylamino)-alkoxycarbonylalkyl,((N-protected)alkylamino)alkoxycarbonyl-alkylamino,(dialkylamino)alkoxycarbonylalkyl,(dialkylamino)alkoxycarbonylalkylamino, aminocycloalkyl,aminoalkylamino, dialkylaminoalkyl(alkyl)amino, arylalkylamino,arylalkyl(alkyl)amino, alkoxyalkyl(alkyl)amino,polyalkyoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino,di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy,(polyalkoxy)alkyl, (heterocyclic)alkyl or a substituted or unsubstitutedheterocyclic wherein saturated heterocyclics may be unsubstituted,monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino,dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturatedheterocyclics may be unsubstituted or monosubstituted with hydroxy,amino, alkylamino, dialkylamino, alkoxy, polyalkoxy or loweralkyl;

W_(f) is C═O or CHOH;

U_(f) is CH₂ or NR_(2f) provided that when W_(f) is CHOH then U_(f) isCH₂ ; R_(1f) is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl,halobenzyl, (1-naphthyl)methyl,(2-napthyl)methyl,(4-imidazolyl)methyl,(alpha,alpha)-dimethylbenzyl,1-benzyloxyethyl,phenethyl, phenoxy, thiophenoxy or anilino; provided that when R_(1f) isphenoxy, thiophenoxy or anilino, then B_(f) is CH₂ or CHOH or A_(f) ishydrogen;

R_(2f) is hydrogen or loweralkyl;

R_(3f) is loweralkyl, loweralkenyl,((alkoxy)alkoxy)loweralkyl,(thioalkoxy)alkyl, benzyl or heterocyclic ring substituted methyl;

R_(6f) is loweralkyl, cycloalkylmethyl or benzyl;

R_(af) is vinyl, formyl, hydroxymethyl or hydrogen;

R_(df) is hydrogen or loweralkyl;

R_(bf) and R_(ef) are independently selected from PH and NH₂ ; and

R_(cf) is hydrogen, loweralkyl, vinyl or arylalkyl; ##STR14## whereinA_(g) is hydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl,dialkylaminoalkyl, (alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl,phenylalkyl, (substituted phenyl)alkyl wherein the phenyl ring issubstituted with one, two or three substituents independently selectedfrom loweralkoxy, loweralkyl, amino, alkylamino, dialkylamino, hydroxy,halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy,alkoxycarbonyl and carboxamide, naphthylalkyl, (substitutednaphthyl)alkyl wherein the naphthyl ring is substituted with one, two orthree substituents independently selected from loweralkoxy, loweralkyl,amino, alkylamino, dialkylamino, hydroxy, halo, mercapto, nitro,thioalkoxy, carboxaldehyde, carboxy, alkoxycarbonyl and carboxamide,substituted or unsubstituted heterocyclic, where saturated heterocyclicsmay be unsubstituted, monosubsituted or disubstituted with hydroxy, oxo,amino, alkylamino, dialkylamino, alkoxy, polyalkoxy, loweralkyl,haloalkyl or polyhaloalkyl; unsaturated heterocyclics may beunsubstituted or monosubstituted with hydroxy, amino, alkylamino,dialkyamino, alkoxy, polyalkoxy, loweralkyl, haloalkyl or polyalkyl, orA₉ is (unsubstituted heterocyclic)alkyl or (substitutedheterocyclic)alkyl wherein unsubstituted or substituted heterocyclic isas defined above, or A_(g) is --OR_(7g) or --SR_(7g) wherein R_(7g) ishydrogen, loweralkyl, aminoalkyl, (alkyl)aminoalkyl, dialkylaminoalkyl,(alkoxy)aminoalkyl, (alkoxy)(alkyl)aminoalkyl, phenylalkyl, (substitutedphenyl)alkyl wherein substituted phenyl is as defined above,naphthylalkyl, (substituted naphthyl)alkyl wherein the substitutednaphthyl is as defined above, substituted or unsubstituted heterocyclicas defined above, (unsubstituted heterocyclic)alkyl or (substitutedheterocyclic)alkyl wherein unsubstituted or substituted heterocyclic isas defined above, (unsubstituted heterocyclic)C(O)-- or (substitutedheterocyclic)C(O)wherein unsubstituted or substituted heterocyclic is asdefined above;

or A_(g) is --NR_(8g) R_(9g) wherein R_(8g) and R_(9g) are independentlyselected from hydrogen, hydroxy, alkoxy, loweralkyl, aminoalkyl,cyanoalkyl and hydroxyalkyl; or A_(g) is ##STR15## wherein B_(g) is NH,alkylamino, S, O, CH₂ or CH(OR_(52g)) ) wherein R_(52g) is hydrogen,loweralkyl or loweralkylcarbonyl, and R_(10g) is hydrogen, loweralkyl,cycloalkyl, phenyl, substituted phenyl as defined above, naphthyl,substituted naphthyl as defined above, alkoxy, alkenyloxy,hydroxyalkoxy, dihydroxyalkoxy, phenylalkoxy, (substituted phenyl)alkoxywherein substituted phenyl is as defined above, naphthylalkoxy,(substituted naphthyl)alkoxy wherein substituted naphthyl is as definedabove, phenylalkoxyalkyl, (substituted phenyl)alkoxyalkyl whereinsubstituted phenyl is as defined above, naphthylalkoxyalkyl,(substituted naphthyl)alkoxyalkyl wherein substituted naphthyl is asdefined above, thioalkoxyalkyl, loweralkylsulfinylalkyl,loweralkylsulfonyalkyl, phenylthioalkyl, (substitutedphenyl)thioalkylwherein substituted phenyl is as defined above, naphthylthioalkyl,(substituted napthyl)thioalkyl wherein substituted napthyl is as definedabove, phenylsulfonyalkyl, (substituted phenyl)sulfonyalkyl whereinsubstituted phenyl is as defined above, naphthylsulfonyalkyl,(substituted naphthyl) sulfonyalkyl wherein substituted napthyl is asdefined above, amino, alkylamino, dialkylamino,(hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl,alkoxycarbonylalkyl, carboxyalkyl,(N-protected)aminoalkyl,alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl,(heterocyclic)alkyl, a substituted or unsubstituted heterocyclic asdefined above, aminocycloalkyl, aminoalkylamino,(dialkylaminoalkyl)(alkyl)amino, phenylalkylamino, (substitutedphenyl)alkylamino wherein substituted phenyl is as defined above,naphthylalkylamino,(substituted naphthyl)alkylamino wherein substitutednaphthyl is as defined above,(phenylalkyl)(alkyl)amino,((substitutedphenyl)alkyl)(alkyl)amino wherein substituted phenyl is as definedabove, (naphthylalkyl)(alkyl)amino, ((substitutednaphthyl)alkyl)(alkyl)amino wherein substituted naphthyl is as definedabove, alkoxyalkyl(alkyl)amino, (polyalkoxy)alkyl(alkyl)amino,di-(alkoxyalkyl)amino, di-(hydroxyalkyl)amino,di-((polyalkoxy)alkyl)amino, ((heterocyclic)alkyl)(alkyl)amino,((heterocyclic)alkyl)amino, (heterocyclic)(alkyl)amino,(alkylaminoalkyl)(alkyl)amino, (dialkylaminoalkyl)(alkyl)amino,((alkoxy)(alkyl)aminoalkyl)alkyl)amino,((alkoxy)aminoalkyl)(alkyl)amino, polyalkoxy or (polyalkoxy)alkyl; orA_(g) is R_(41g) CH(OH)CH₂ -- or R_(41g) CH(OH)CH(OH)-- wherein R_(41g)is loweralkyl, cycloalkyl, phenyl, substituted phenyl as defined above,napthyl, substituted naphthyl as defined above, phenylalkyl,(substituted phenyl)alkyl wherein substituted phenyl is as definedabove, naphthylalkyl, (substituted naphthyl)alkyl wherein substitutednaphthyl is as defined above, phenylalkoxyalkyl, (substitutedphenyl)alkoxyalkyl wherein substituted phenyl is as defined above,naphthylalkoxyalkyl, (substituted napthyl)alkoxyalkyl whereinsubstituted naphthyl is as defined above, thioalkoxyalkyl,loweralkylsulfinylalkyl, loweralkylsulfonylalkyl, phenylthioalkyl,(substitutedphenyl)thioalkyl wherein substituted phenyl is as definedabove, naphthylthioalkyl, (substituted naphthyl)thioalkyl whereinsubstituted naphthyl is as defined above, phenylsulfonyalkyl,(substituted phenyl)sulfonyalkyl wherein substituted phenyl is asdefined above, naphthylsulfonyalkyl, (substituted naphthyl)sulfonyalkylwherein substituted naphthyl is as defined above, aminoalkyl,alkoxycarbonylalkyl, carboxyalkyl, (N-protected)aminoalkyl,alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl,heterocyclicalkyl, a substituted or unsubstituted heterocyclic asdefined above, aminocycloalkyl or (polyalkoxy)alkyl;

W_(g) is C═O, CHOH or NR_(2g) wherein R_(2g) is hydrogen or loweralkyl;

U_(g) is C═O, CH₂ or NR_(2g) wherein R_(2g) is hydrogen or loweralkyl,with the proviso that when W_(g) is CHOH then U_(g) is CH₂ and with theproviso that U_(g) is C═O or CH₂ when W_(g) is NR_(2g) ;

V_(g) is CH, C(OH) or C(halogen) with the proviso that V_(g) is CH whenU_(g) is NR_(2g) ;

R_(1g) is loweralkyl, cycloalkylalkyl, benzyl,(alpha,alpha)-dimethylbenzyl,4-methoxybenzyl, halobenzyl,4-hydroxybenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl, (unsubstitutedheterocyclic)methyl,(substituted heterocyclic)methyl whereinunsubstituted or substituted heterocyclic is as defined above,phenethyl, 1-benzyloxyethyl, phenoxy, thiophenoxy or anilino, providedthat B_(g) is CH₂ or CHOH or A_(g) is hydrogen when R_(1g) is phenoxythiophenoxy or anilino;

R_(3g) is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl,(thioalkoxy)alkyl, azidoalkyl, aminoalkyl, (alkyl)aminoalkyl,dialkylaminoalkyl, (alkoxy)(alkyl)aminoalkyl, (alkoxy)aminoalkyl, benzylor heterocyclic ring substituted methyl;

R_(4g) is loweralkyl, cycloalkylmethyl or benzyl;

R_(5g) is OH or NH₂ ; and

Z_(g) is ##STR16## wherein M_(g) is O, S, or NH, T_(g) is C═O, C═S, S,S, S(O), S(O)₂ or CH₂, E_(g) is O, S, NR_(6g) wherein R_(6g) ishydrogen, loweralkyl, hydroxyalkyl, hydroxy, alkoxy, amino, oralkylamino, or E_(g) is CR_(6g) R_(42g) wherein R_(6g) is as definedabove and R_(42g) is hydrogen or loweralkyl or E_(g) is C≡CR_(43g)R_(44g) wherein R_(43g) and R_(44g) are independently selected fromhydrogen and loweralkyl, G_(g) is absent, CH₂ or NR_(11g) whereinR_(11g) is hydrogen or loweralkyl, with the proviso that when G_(g) isNR_(11g) then R_(6g) is loweralkyl or hydroxyalkyl, Q_(g) is CR_(45g)R_(46g) wherein R_(45g) and R_(46g) are independently selected fromhydrogen and loweralkyl or Q_(g) is C═CR_(47g) R_(48g) wherein R_(47g)and R_(48g) are independently selected from hydrogen and loweralkyl, andR_(49g) is --CH₂ OH, carboxy, alkoxycarbonyl or --CONR_(50g) R_(51g)wherein R_(50g) is hydrogen or loweralkyl and R_(51g) is hydrogen,loweralkyl, aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl oralkoxyalkyl; ##STR17## wherein A _(h) is hydrogen, loweralkyl,arylalkyl, --OR_(20h) or --SR_(20h) wherein R20h is hydrogen, loweralkylor aminoalkyl, --NR_(21h) R_(22h) wherein R_(21h) and R_(22h) areindependently selected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyland hydroxyalkyl; or A_(h) is ##STR18## wherein B_(h) is NH, alkylamino,S, O, CH₂ NHCH₂ or CHOH; and R_(23h) is loweralkyl, cycloalkyl, aryl,arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy,arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkyalmino,(hydroxyalkyl)(alkyl)amino, ((dialkylamino)alkyl)(alkyl)amino,(dihydroxyalkyl)(alkyl)amino, aminoalkyl, N-protected aminoalkyl,alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl, dialkylaminoalkyl,(heterocyclic)alkyl, or a substituted or unsubstituted heterocyclic;

W_(h) is C═O or CHOH;

U_(h) is CH₂ or NR_(2h) wherein R_(2h) is hydrogen or loweralkyl,provided that when W_(h) is CHOH then U_(h) is CH₂ ;

R_(1h) is loweralkyl, cycloalkylalkyl, benzyl, 4-methoxybenzyl,4-hydroxybenzyl, halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl,(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl,phenethyl, phenoxy, thiophenoxy or anilino, provided that when R_(1h) isphenoxy, thiophenoxy or anilino, then B_(h) is CH₂ or CHOH or A_(h) ishydrogen;

R_(3h) is loweralkyl, loweralkenyl, ((alkoxy)alkoxy)alkyl, carboxyalkyl,(thioalkyoxy)alkyl, benzyl or heterocyclic ring substituted methyl;

R_(5h) is hydrogen or loweralkyl;

R_(6h) is loweralkyl, cycloalkylmethyl, or benzyl; ##STR19## whereinA_(i) is (I) R_(5i) C(O)--(CH₂)_(w") " wherein

1) w" is 0 to 4 and

2)R_(5i) is

i) hydroxy,

ii) alkoxy,

iii) thioalkoxy,

iv) amino or

v) substituted amino;

(II) alkylsulfonyl, (aryl)sulfonyl or (heterocyclic)sulfonyl;

(III) aryl, arylalkyl, heterocyclic or (heterocyclic)alkyl; or

(IV) R_(90i) -- or R_(90i) NHC(O)-- wherein R_(90i) is a C₁ to C₄straight or branched carbon chain substituted by a substituent selectedfrom

1) carboxy,

2) alkoxycarbonyl,

3) alkylsulfonyl,

4) aryl,

5) arylsulfonyl,

6) heterocyclic or

7) (heterocyclic)sulfonyl);

R_(1i) is

(I) hydrogen

(II) loweralkyl,

(II) loweralkenyl,

(IV) cycloalkylalkyl

(V) cycloalkenyalkyl,

(VI) aryloxyalkyl,

(VII) thioaryloxyalkyl,

(IV) arylalkoxyalkyl,

(IX) arylthioalkoxyalkyl or

(X) a C₁ to C₃ straight or branched carbon chain substituted by asubstituent selected from

1) alkoxy,

2) thioalkoxy,

3) aryl and

4) heterocyclic;

X_(i) is

(I) CH₂,

(II) CHOH,

(III) C(O),

(IV) O,

(VI) S,

(VII) S(O),

(VIII) SO₂,

(IX) N(O) or

(X) --P(O)--;

R_(3i) is

(I) loweralkyl,

(II) haloalkyl,

(III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenyalkyl,

(VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VII) (alkoxyalkoxy)alkyl,

(IX) hydroxyalkyl,

(X) --(CH₂)_(ee) NHR_(12i) wherein

1) ee is 1 to 3 and

2) R_(12i) is

i) hydrogen,

ii) loweralkyl or

iii) an N-protecting group;

(XI arylalkyl or

(XII) (heterocyclic)alkyl; and

T_(i) is ##STR20## wherein R_(4i) is (I) loweralkyl,

(II) cycloalkylalkyl

(III) cycloalkenyalkyl or

(IV) arylalkyl; and

D_(i) is ##STR21## wherein R_(73i) is loweralkyl, ##STR22## wherein 1)M_(i) is

i) O,

ii) S or

iii) NH;

2) Q_(i) is

i) O or

ii) S;

3) E_(i) is

i) O,

ii) S,

iii) CHR_(73i) wherein R_(73i) is loweralkyl,

iv) C═CH₂ or

v) NR_(18i) wherein R_(18i) is

a) hydrogen,

b) loweralkyl,

c) hydroxyalkyl,

d) hydroxy,

e) alkoxy,

f) amino or

g) alkylamino;

and

4) G_(i) is

i) absent,

ii) CH₂ or

iii) NR_(19i) wherein R_(19i) is hydrogen or loweralkyl, with theproviso that when G_(i) is NR_(19i), then R_(18i) is loweralkyl orhydroxyalkyl; ##STR23## wherein 1) v" is 0 or 1 and

2) R_(21i) is

i) NH,

ii) O,

iii) S or

iv) SO₂ ; or

(IV) a substituted methylene group; and ##STR24## wherein X_(j) is (I)N,

(II) O or

(III) CH;

R_(1j) is

(I) absent,

(II) hydrogen,

(III) an N-protecting group,

(IV) aryl,

(V) heterocyclic, or

(VI) R_(6j) --Q_(j) -- wherein

1) R_(6j) is

i) loweralkyl,

ii) amino,

iii) alkylamino,

iv) dialkylamino,

v) (alkoxyalkyl)(alkyl)amino,

vi) (alkoxyalkoxyalkyl)(alkyl)amino,

vii) aryl,

viii) arylalkyl,

ix) aminoalkyl,

x) (N-protected)aminoalkyl,

xi) alkoxy,

xii) substituted loweralkyl wherein the substituent is selected fromalkoxy, thioalkoxy, halogen, alkylamino, (N-protected)(alkyl)amino anddialkylamino, ##STR25## wherein m"' is 1 to 5 and R_(7j) is hydrogen,alkoxy, thioalkoxy, alkoxyalkoxy, polyalkoxy, amino, (N-protected)amino,alkylamino, (N-protected)(alkyl)amino or dialkylamino; or ##STR26##wherein R_(8j) is O, S, SO₂, O═C or R_(9j) N wherein R_(9j) is hydrogen,loweralkyl or an N-protecting group; and

2) Q_(j) is

i) C═O or

ii) CH₂,

with the proviso that X_(j) is N when R_(1j) is an N-protecting group;

(VII) R_(54j) S(O)₂ -- wherein R_(54j) is

1) amino

2) alkylamino,

3) dialkylamino,

4) loweralkyl,

5) haloalkyl,

6) aryl,

7) p-biphenyl,

8) heterocyclic or

VIII) (R_(55j))₂ P(O)-- wherein R_(55j) is

1) alkoxy,

2) alkylamino or

3) dialkylamino;

A_(j) and L_(j) are independently selected from

(I) absent,

(II) C═O,

(III) SO₂ and

(IV) CH₂ ;

D_(j) is

(I) C═O,

(II) SO₂ or

(III) CH2;

Y_(j) is

(I) N or

(II) CH;

R_(2j) is

(I) hydrogen,

(II) loweralkyl,

(III) cycloalkylalkyl,

(IV) --CH₂ --R_(10j) --(CH₂)_(q"') --R_(11j) wherein

1) q"' is 0, 1 or 2,

2) R_(10j) is absent or R_(10j) is O, NH or S only when q"' is 1 or 2,and

3) R_(11j) is

i) aryl or

ii) heterocyclic;

Z_(j) is

(I) hydrogen or

(I) --R_(28j) C(O)R_(29j') --R_(28j) S(O)₂ R_(29j) or --R_(28j)C(S)R_(29j) wherein

1) R_(28j) is

i) NH,

ii) --N(R_(200j))-- wherein R_(200j) is loweralkyl or benzyl or

iii) CH₂ and

2) R_(29j) is

i) alkoxy,

ii) benzyloxy,

iii) alkylamino,

iv) dialkylamino,

v) aryl or

vi) heterocyclic;

R_(3j) is

(I) hydrogen,

(II) loweralkyl,

(III) loweralkenyl,

(IV) cycloalkylalkyl,

(V) cycloalkenyalkyl,

(VI) alkoxyalkyl,

(VII) thioalkoxyalkyl,

(VIII) (alkoxyalkoxy)alkyl,

(IX) (polyalkoxy)alkyl,

(X) arylalkyl or

(XI) (heterocyclic)alkyl;

n"' is 0 or 1; and

T_(j) is ##STR27## wherein R_(4j) is (I) loweralkyl,

(II) cycloalkylalkyl or

(III) arylalkyl; and

R_(5j) is ##STR28## wherein R_(73j) is loweralkyl, ##STR29## wherein 1)M_(j) is

i) O

ii) S or

iii) NH;

2) O_(j) is

i) O or

ii) S;

3) E_(j) is

i) O,

ii) S,

iii) CHR_(61j) wherein R_(61j) is loweralkyl,

iv) C═CH₂ or

v) NR_(18j) wherein R_(18j) is

a) hydrogen,

b) loweralkyl,

c) hydroxyalkyl,

d) hydroxy,

e) alkoxy,

f) amino or

g) alkylamino;

and

4) G_(j) is

i) absent,

ii) CH₂ or

iii) NR_(19j) wherein R_(19j) is hydrogen or loweralkyl, with theproviso that when G_(j) is NR_(19j), then R_(18j) is loweralkyl orhydroxyalkyl; ##STR30## wherein 1) v"' is 0 or 1 and

2) R_(21j) is

i) NH,

ii) O,

iii) S or

iv) SO₂ ; or

(IV) a substituted methylene group;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

The term "loweralkyl" as used herein refers to straight or branchedchain alkyl radicals containing from 1 to 7 carbon atoms including butnot limited to methyl, ethyl, n-propyl, iso-propyl, n-butyl, iso-butyl,sec-butyl, n-pentyl, 2-methylbutyl, 2,2-dimethylpropyl, n-hexyl,2-methyl-pentyl, 2,2-dimethylbutyl, n-heptyl, 2-methylhexyl and thelike.

The term "loweralkenyl" as used herein refers to a straight or branchedchain loweralkyl radical which contains at least one carbon-carbondouble bond.

The term "cycloalkyl" as used herein refers to an aliphatic ring having3 to 7 carbon atoms.

The term "cycloalkylalkyl" as used herein refers to a cycloalkyl residueappended to a loweralkyl radical and includes but is not limited tocyclohexylmethyl and cyclopentylmethyl.

The term "cycloalkenyl" as used herein refers to an aliphatic ringhaving 3-7 carbon atoms and also having at least one carbon-carbondouble bond including, but not limited to, cyclohexenyl and the like.

The term "cycloalkenylalkyl" as used herein refers to a cycloalkenylgroup appended to a loweralkyl radical including, but not limited to,cyclohexenylmethyl, cyclopentenylethyl and the like.

The term "aryalkyl" as used herein refers to an aryl group as definedherein appended to a loweralkyl radical including but not limited tobenzyl, 1- and 2-naphthylmethyl, halobenzyl, and alkoxybenzyl.

The term "phenyalkyl" as used herein refers to a phenyl group appendedto a loweralkyl radical, including, but not limited to benzyl, phenethyland the like.

The term "(substituted phenyl)alkyl" as used herein refers to asubstituted phenyl group appended to a loweralkyl radical wherein thephenyl ring is substituted with one, two or three substituents chosenfrom the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy,halo, mercapto, nitro thialkoxy, carboxaldehyde, carboxy, carboalkoxyand carboxamide, including, but not limited to halobenzyl, alkoxybenzyland the like.

The term "naphthylalkyl" as used herein refers to a naphthyl groupappended to a loweralkyl radical, including but not limited to1-naphthylmethyl, 2-napthylmethyl and the like.

The term "(substituted naphthyl)alkyl" as used herein refers to asubstituted napthyl group appended to a loweralkyl radical wherein thenaphthyl ring is substituted with one, two or three substituents chosenfrom the group loweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy,halo, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxyand carboxamide, including, but not limited to halonaphthylmethyl,alkoxynaphthylmethyl and the like.

The term "(heterocyclic)alkyl" as used herein refers to an unsubstitutedor substituted heterocyclic ring as defined below appended to aloweralkyl radical, including, but not limited to imidazolylmethyl,thiazolylmethyl and the like.

The term "hydroxyalkyl" as used herein refers to --OH appended to aloweralkyl radical.

The term "alkoxyalkyl" as used herein refers to an alkoxy group appendedto a loweralkyl radical.

The term "arylalkoxyalkyl" as used herein refers to an arylalkoxyappended to a lower radical.

The term "phenylalkoxyalkyl" as used herein refers to a phenylalkoxygroup appended to a loweralkyl radical, including, but not limited tophenylmethoxymethyl and the like.

The term "(substituted phenyl)alkoxyalkyl" as used herein refers to a(substituted phenyl)alkoxy group appended to a loweralkyl radical,including, but not limited to 4-chlorophenylmethoxymethyl.

The term "naphthylalkoxyalkyl" as used herein refers to a naphthylalkoxygroup appended to a loweralkyl radical, including, but not limiting to1-naphthylmethoxymethyl and the like.

The term "substituted naphthyl)alkoxyalkyl" as used herein refers to a(substituted naphthyl)alkoxy group appended to a loweralky radical,including, but not limited to halonaphthylmethoxymethyl and the like.

The term "thioalkoxyalkyl" as used herein refers to a thioalkoxy groupappended to a loweralkyl radical.

The term "((alkoxy)alkoxy)alkyl" as used herein refers to an alkoxygroup appended to an alkoxy group which is appended to a loweralkylradical, including, but not limited to methoxymethoxymethyl and thelike.

The term "polyalkoxyalkyl" as used herein refers to a polyalkoxy residueappended to a loweralkyl radical, including, but not limited tomethoxyethyoxymethoxymethyl and the like.

The term "aminoalkyl" as used herein refers to --NH₂ appended to aloweralkyl radical.

The term "alkylaminoalkyl" as used herein refers to --NHR₇₀ appended toa loweralkyl radical, wherein R₇₀ is a loweralkyl radical.

The term "dialkylaminoalkyl" as used herein refers to a dialkylaminoappended to a loweralkyl radical.

The term "aminocycloalkyl" as used herein refers to an --NH₂ appended toa cycloalkyl radical.

The term "N-protected aminoalkyl" as used herein refers to --NHR₇₁appended to a loweralkyl group, wherein R₇₁ is an N-protecting group.

The term "(N-protected)(alkyl)amino alkyl" as used herein refers to--NR₇₁ R₇₂ which is appended to a loweralkyl radical, wherein R₇₁ isdefined as above and R₇₂ is a loweralkyl group.

The term "alkoxycarbonyalkyl" as used herein refers to R₇₃ C(O)R₇₄ --wherein R₇₃ is an alkoxy group and R₇₄ is a loweralkyl radical.

The term "carboxyalkyl" as used herein refers to a carboxylic acid group(--COOH) appended to a loweralkyl radical.

The term "cyanoalkyl" as used herein refers to --CN appended to aloweralkyl radical.

The term "axidoalkyl" as used herein refers to --N₃ appended to aloweralkyl radical.

The term "(alkoxy)aminoalkyl" as used herein refers to an alkoxy groupappended to an amino group which in turn is appended to a loweralkylradical.

The term "(alkoxy)(alkyl)aminoalkyl" as used herein refers to an --NR₇₅R₇₆ group appended to a loweralkyl radical wherein R₇₅ is an alkoxygroup and R₇₆ is a loweralkyl group.

The term "loweralkylsulfinyalkyl" as used herein refers to a R₇₇ S(O)--group appended to a loweralkyl radical wherein R₇₇ is a loweralkylgroup.

The term "loweralkylsulfonylalkyl" as used herein refers to a R₇₈ S(O)₂-- group appended to a loweralkyl radical wherein R₇₈ is a loweralkylgroup.

The term "phenylthioalkyl" as used herein refers to a R₇₉ S-- groupappended to a loweralkyl radical wherein R₇₉ is a phenyl group.

The term "(substituted phenyl)thioalkyl" as used herein refers to a R₈₀S-- group appended to a loweralkyl radical wherein R₈₀ is a substitutedphenyl group.

The term "naphthyl thioalkyl" as used herein refers to a R₈₁ S-- groupappended to a loweralkyl radical wherein R₈₁ is a naphthyl group.

The term "(substituted naphthyl)thioalkyl" as used herein refers to aR₈₂ S-- group appended to a loweralkyl radical wherein R₈₂ is asubstituted naphthyl group.

The term "phenylsulfonylalkyl" as used herein refers t a R₈₃ S(O)₂ --group appended to a loweralkyl radical wherein R₈₃ is a phenyl group.

The term "(substituted phenyl)sulfonyalkyl" as used herein refers to aR₈₄ S(O)₂ -- group appended to a loweralkyl radical wherein R84 is asubstituted phenyl group.

The term "naphthylsulfonylalkyl" as used herein refers to a R₈₅ S(O)₂ --group appended to a loweralkyl group wherein R₈₅ is a naphthyl group.

The term "(substituted naphthyl)sulfonylalkyl" as used herein refers toa R₈₆ S(O)₂ -- group appended to a loweralkyl group wherein R₈₆ is asubstituted naphthyl group.

The term "carboxyalkoxyalkyl" as used herein refers to a carboxylic acidgroup (--COOH) appended to a n alkoxy group which is appended to aloweralkyl radical.

The term "alkoxycarbonylalkoxyalkyl" as used herein refers to analkoxycarbonyl group (R₈₇ CO-- wherein R₈₇ is an alkoxy group) appendedto an alkoxy group which is appended to a loweralkyl radical.

The term "(amino)carboxyalkyl" as used herein refers to a loweralkylradical to which is appended a carboxylic acid group (--COOH) and anamino group (--NH₂).

The term "((N-protected)amino)carboxyalkyl" as used herein refers to aloweralkyl radical to which is appended a carboxylic acid group (--COOH)and --NHR₈₈ wherein R₈₈ is an N-protecting group.

The term "(alkylamino)carboxyalkyl" as used herein refers to aloweralkyl radical to which is appended a carboxylic acid group (--COOH)and an alkylamino group.

The term "((N-protected)alkylamino)-carboxyalkyl" as used herein refersto a loweralkyl radical to which is appended a carboxylic acid group(--COOH) and an --NR₈₉ R₉₀ wherein R₈₉ is as defined above and R₉₀ is aloweralkyl group.

The term "(dialkylamino)carboxyalkyl" as used herein refers to aloweralkyl radical to which is appended a carboxylic acid group (--COOH)and --NR₉₁ R₉₂ wherein R₉₁ and R₉₂ are independently selected fromloweralkyl.

The term "(amino)alkoxycarbonylalkyl" as used herein refers to aloweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and an amino group (--NH₂).

The term "((N-protected)amino)alkoxycarbonylalkyl" as used herein refersto a loweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and --NHR₉₃ wherein R₉₃ is as defined above.

The term "(alkylamino)alkoxycarbonylalkyl" as used herein refers to aloweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and an alkylamino group as defined above.

The term "((N-protected)alkylamino)alkoxycarbonylalkyl" as used hereinrefers to a loweralkyl radical to which is appended an alkoxycarbonylgroup as defined above and --NR₉₄ R₉₅ wherein R₉₄ is an N-protectinggroup and R₉₅ is a loweralkyl group.

The term "(dialkylamino)alkoxycarbonyalkyl" as used herein refers to aloweralkyl radical to which is appended an alkoxycarbonyl group asdefined above and --NR₉₆ R₉₇ wherein R₉₆ and R₉₇ are independentlyselected from loweralkyl.

The term "carboxyalkylamino" as used herein refers to --NHR₉₈ whereinR₉₈ is a carboxyalkyl group.

The term "alkoxycarbonylalkylamino" as used herein refers to --NHR₉₉wherein R₉₉ is an alkoxycarbonylalkyl group.

The term "(amino)carboxyalkylamino" as used herein refers to --NHR₁₀₀wherein R₁₀₀ is an (amino)carboxyalkyl group.

The term "((N-protected)amino)carboxyalkylamino" as used herein refersto --NHR₁₀₁ wherein R₁₀₁ is an ((N-protected)amino)carboxyalkyl group.

The term "(alkylamino)carboxyalkylamino" as used herein refers to--NHR₁₀₂ wherein R₁₀₂ is an (alkylamino)carboxyalkyl group.

The term "((N-protected)alkylamino)-carboxyalkylamino" as used hereinrefers to --NHR₁₀₃ wherein R₁₀₃ is an((N-protected)alkylamino)carboxyalkyl group.

The term "(dialkylamino)carboxyalkylamino" as used herein refers to--NHR₁₀₄ wherein R₁₀₄ is a (dialkylamino)carboxyalkyl group.

The term "(amino)alkoxycarbonylalkylamino" as used herein refers to--NHR₁₀₅ wherein R₁₀₅ is an (amino)alkoxycarbonylalkyl group.

The term "((N-protected)amino)alkoxycarbonylalkylamino" as used hereinrefers to --NHR₁₀₆ wherein R₁₀₆ is an((N-protected)amino)alkoxycarbonylalkyl group.

The term "(alkylamino)alkoxycarbonylalkylamino" as used herein refers to--NHR₁₀₇ wherein R₁₀₇ is an (alkylamino)alkoxycarbonylalkyl group.

The term "((N-protected)alkylamino)alkoxycarbonylalkylamino" as usedherein refers to --NHR₁₀₈ wherein R₁₀₈ is an((N-protected)alkylamino)alkoxycarbonylalkyl group.

The term "(dialkylamino)alkoxycarbonylalkyl group.

The term "alkylidene" as used herein refers to a straight or branchedchain alkyl radical which is attached via a carbon-carbon double bondand includes but is not limited to methylidene, ethylidene,1-propylidene, 1-butylidene, 1-pentylidene, 2-propylidene, 2-butylidene,2-pentylidene, 3-pentylidene, 3-hexylidene, 3-heptylidene and4-heptylidene.

The term "alkylidene oxide" as used herein refers to an epoxide moietywhich is derived from an alkylidene group.

The term "amino" as used herein refers to an --NH₂ substituents. Theterm "alkylamino" as used herein refers to --NHR₁₁₀, wherein R₁₁₀ is aloweralkyl group.

The term "dialkylamino" as used herein refers to --NR₁₁₁ R₁₁₂ whereinR₁₁₁ and R₁₁₂ are independently selected from loweralkyl groups.

The term "arylalkylamino" as used herein refers to R₁₁₃ NH--, whereinR₁₁₃ is an arylalkyl residue.

The term "arylalkyl(alkyl)amino" as used herein refers to R₁₁₄ R₁₁₅ N--,wherein R₁₁₄ is an arylalkyl residue and R₁₁₅ is a loweralkyl residue.

The term "phenylalkylamino" as used herein refers to a phenylalkyl groupappended to an amino radical, including but not limited to benzylaminoand the like.

The term "(substituted phenyl)alkylamino" as used herein refers to a(substituted phenyl)alkyl group appended to an amino radical, including,but not limited to 4-chlorobenzylamino and the like.

The term "naphthylalkylamino" as used herein refers to a naphthylalkylgroup appended to an amino radical, including, but not limited to1-naphthylmethylamino and the like.

The term "(substituted naphthyl)alkylamino" as used herein refers to a(substituted naphthyl)alkyl group appended to an amino radical.

The term "(phenylalkyl)(alkyl)amino" as used herein refers to R₁₁₆ R₁₁₇N--, wherein R₁₁₆ is a phenylalkyl residue and R₁₁₇ is a loweralkylresidue.

The term "((substituted phenyl)alkyl)-(alkyl)amino" as used hereinrefers to R₁₁₈ R₁₁₉ N-- wherein R₁₁₈ is a (substituted phenyl)alkylgroup and R₁₁₉ is a loweralkyl group.

The term "(naphthylalkyl)(alkyl)amino" as used herein refers to R₁₂₀R₁₂₁ N-- wherein R₁₂₀ is a naphthylalkyl group and R₁₂₁ is a loweralkylgroup.

The term "((substituted naphthyl)alkyl)(alkyl)amino" as used hereinrefers to R₁₂₂ R₁₂₃ N-- wherein R₁₂₂ is a (substituted naphthyl)alkylgroup and R₁₂₃ is a loweralkyl group.

The term "aminoalkylamino" as used herein refers to R₁₂₄ NH-- where R₁₂₄is an aminoalkyl residue.

The term "dialkylamino(alkyl)amino" as used herein refers to R₁₂₅ R₁₂₆N--, wherein R₁₂₅ is a dialkylamino residue appended to a loweralkylresidue and R₁₂₆ is a loweralkyl residue.

The term "((dialkylamino)alkyl)(alkyl)amino" as used herein refers to--NR₁₂₇ R₁₂₈ wherein R₁₂₇ is a dialkylamino residue appended to aloweralkyl residue and R₁₂₈ is a loweralkyl residue.

The term "(hydroxyalkyl)(alkyl)amino" as used herein refers to --NR₁₂₉R₁₃₀ wherein R₁₂₉ is a hydroxylalkyl group and R₁₃₀ is a loweralkylgroup.

The term "(di-hydroxyalkyl)(alkyl)amino" as used herein to a loweralkylgroup which is disubstituted with --OH radicals appended to an aminogroup, which amino group also has appended another loweralkyl group.

The term "di-(hydroxyalkyl)amino" as used herein refers to R₁₃₁ R₁₃₂N--, wherein R₁₃₁ and R₁₃₂ are hydroxyalkyl residues.

The term "alkoxyalkyl(alkyl)amino" as used herein refers to R₁₃₃ R₁₃₄N--, wherein R₁₃₃ is a loweralkyl group and R₁₃₄ is an alkoxyalkylgroup.

The term "di-(alkoxyalkyl)amino" as used herein refers to R₁₃₅ R₁₃₆ N--,wherein R₁₃₅ and R₁₃₆ are alkoxy residue appended to a loweralkylresidues.

The term "di-(polyalkoxyalkyl)amino" as used herein refers to R₁₃₇ R₁₃₈N--, wherein R₁₃₇ and R₁₃₈ are polyalkoxy residues appended toloweralkyl residues.

The term "((polyalkoxy)alkyl)(alkyl)amino" as used herein refers to R₁₃₉R₁₄₀ N--, wherein R₁₃₉ is a polyalkoxy residue appended to a loweralkylradical and R140 is a loweralkyl residue.

The term "((heterocyclic)alkyl)(alkyl)amino" as used herein refers to--NR₁₄₁ R₁₄₂ wherein R₁₄₁ is a heterocyclic group and R₁₄₂ is aloweralkyl group.

The term "(heterocyclicalkyl)amino" as used herein refers to --NHR₁₄₃wherein R₁₄₃ is a heterocyclic alkyl group.

The term "(heterocyclic)(alkyl)amino" as used herein refers to --NR₁₄₄R₁₄₅ wherein R₁₄₄ is a substituted or unsubstituted heterocyclic groupand R₁₄₅ is a loweralkyl group.

The term "(alkylaminoalkyl)(alkyl)amino" as used herein refers to--NR₁₄₆ R₁₄₇ wherein R₁₄₆ is an alkylaminoalkyl group and R₁₄₇ is aloweralkyl group.

The term "(dialkylaminoalkyl)(alkyl)amino" as used herein refers to--NR₁₄₈ R₁₄₉ wherein R₁₄₈ is a dialkylaminoalkyl group and R₁₄₉ is aloweralkyl group.

The term "((alkoxy)(alkyl)aminoalkyl)--(alkyl)amino" as used hereinrefers to --NR₁₅₀ R₁₅₁ wherein R₁₅₀ is --NR₁₅₂ R₁₅₃ appended to aloweralkyl radical wherein R₁₅₂ is an alkoxy group and R₁₅₃ is aloweralkyl group and R₁₅₁ is a loweralkyl group.

The term "((alkoxy)aminoalkyl)(alkyl)amino" as used herein refers to--NR₁₅₄ R₁₅₅ wherein R₁₅₄ is --NHR₁₅₆ appended to a loweralkyl group andwherein R₁₅₆ is an alkoxy group and R₁₅₅ is a loweralkyl group.

The term "(alkoxyalkoxyalkyl)(alkyl)amino" as used herein refers to--NR₃₀₅ R₃₀₆ wherein R₃₀₅ is an alkoxyalkoxyalkyl group and R₃₀₆ is aloweralkyl group.

The term "di(alkoxyalkoxyalkyl)amino" as used herein refers to --NR₃₀₇R₃₀₈ wherein R₃₀₇ and R₃₀₈ are alkoxyalkoxyalkyl groups.

The term "alkylsulfonylamino" as used herein refers to R₃₀₉ NH-- whereinR₃₀₉ is an alkylsulfonyl group.

The term "arylsulfonylamino" as used herein refers to R₃₁₀ NH-- whereinR₃₁₀ is an arylsulfonyl group.

The term "alkylaminocarbonylamino" as used herein refers to R₃₁₁C(O)NH-- wherein R₃₁₁ is an alkylamino group.

The term "alkylaminocarbonyloxy" as used herein refers to R₃₁₂ C(O)O--wherein R₃₁₂ is an alkylamino group.

The term "alkoxycarbonyloxy" as used herein refers to R₃₁₃ C(O)O--wherein R₃₁₃ is an alkoxy group.

The term "loweralkylcarbonyl" as used herein refers to R₁₅₇ C(O)--wherein R₁₅₇ is a loweralkyl group, including, but not limited toacetyl, propionyl and the like.

The terms "alkoxy" and "thioalkoxy" as used herein refer to R₁₅₈ O-- andR₁₅₈ S--, respectively, wherein R₁₅₈ is a loweralkyl group.

The term "alkoxyalkoxy" as used herein refers to an alkoxy groupappended to an alkoxy radical including, but not limited to,methoxymethoxy and the like.

The term "aryloxyalkyl" as used herein refers to an aryloxy group (R₃₀₃O-- wherein R₃₀₃ is an aryl group) appended to a loweralkyl radical.

The term "thiaryloxyalkyl" as used herein refers to a thioaryloxy group(R₃₀₄ S-- wherein R₃₀₄ is an aryl group) appended to a loweralkylradical.

The terms "arylalkoxy" and "arylthioalkoxy" as used herein refers to anaryl group appended to an alkoxy radical or a thioalkoxy radical,respectively, including, but not limited to, phenoxymethyl,thiophenoxymethyl and the like.

The terms "arylalkoxyalkyl" and "arylthioalkoxyalkyl" as used hereinrefer to an arylalkoxy group or an arylthioalkoxy group, respectively,appended to a loweralkyl radical.

The term "alkenyloxy" as used herein refers to R₁₅₉ O--, wherein R₁₅₉ isan alkyl group of 1 to 7 carbon atoms which contains at least onecarbon-carbon double bond.

The term "hydroxyalkoxy" as used herein refers to --OH appended to analkoxy radical.

The term "dihydroxyalkoxy" as used herein refers to an alkoxy radicalwhich is disubstituted with --OH radicals.

The term "arylalkoxy" as used herein refers to an aryl group appended toan alkoxy radical.

The term "alkylaryloxy" as used herein refers to R₁₆₀ O-- wherein R₁₆₀is an alkylaryl group.

The term "phenylalkoxy" as used herein refers to a phenyl group appendedto an alkoxy radical, including, but not limited to benzyloxy and thelike.

The term "(substituted phenyl)alkoxy" as used herein refers to asubstituted phenyl group appended to an alkoxy radical, including, butnot limited to 4-chlorobenzyloxy and the like.

The term "naphthylalkoxy" as used herein refers to a naphthyl groupappended to an alkoxy radical.

The term "(substituted naphthyl)alkoxy" as used herein refers to asubstituted naphthyl group appended to an alkoxy radical.

The term "polyalkoxy" as used herein refers to R₁₆₁ O--, wherein R₁₆₁ isa straight or branched chain containing 1-5, C_(m) --O--C_(m), linkageswhere m and m' are independently 1 to 3.

The terms "halo" or "halogen" as used herein refer to Cl, Br, F or Isubstituents.

The term "haloalkyl" as used herein refers to a loweralkyl radical inwhich one or more hydrogen atoms are replaced by halogen including, butnot limited to fluoromethyl, 2-chloroethyl, trifluoromethyl,2,2-dichloroethyl and the like.

The term "polyhaloalkyl" as used herein refers to a loweralkyl radicalsubstituted with two or more halogens, including but not limited totrifluoromethyl, 2,2-dichloroethyl and the like.

The term "halobenzyl" as used herein refers to a halo substituentappended to the phenyl ring of a benzyl radical.

The term "halophenyl" as used herein refers to a halo substituentappended to a phenyl radical.

The term "alkylsulfonyl" as used herein to R₃₀₀ S(O)₂ -- wherein R₃₀₀ isa loweralkyl group.

The term "(aryl)sulfonyl" as used herein refers to R₃₀₁ S(O)₂ -- whereinR₃₀₁ is an aryl group.

The term "(heterocyclic)sulfonyl" as used herein refers to R₃₀₂ S(O)₂ --wherein R₃₀₂ is a heterocyclic group.

The term "arylsulfonylalkyl" as used herein refers to an arylsulfonylgroup appended to a loweralkyl radical.

The term "aryl" as used herein refers to a monocyclic or bicycliccarbocyclic ring system having one or more aromatic rings including, butnot limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl and thelike; or "aryl? refers to a heterocyclic aromatic ring as definedherein. Aryl groups can be substituted or substituted with one, two orthree substituents independently selected from loweralkyl, haloalkyl,alkoxy, thioalkoxy, amino, alkylamino, dialkylamino, hydroxy, halo,mercapto, nitro, carboxaldehyde, carboxy, alkoxycarbonyl andcarboxamide.

The term "substituted phenyl" as used herein refers to a phenyl ringsubstituted with one, two or three substituents chosen from the grouploweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo,mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy andcarboxamide, including, but not limited to halophenyl, loweralkylphenyl,alkoxyphenyl and the like.

The term "substituted naphthyl" as used herein refers to a naphthyl ringsubstituted with one, two or three substituents chosen from the grouploweralkoxy, loweralkyl, amino, loweralkylamino, hydroxy, halo,mercapto, nitro, thioalkoxy, carboxaldehyde, carboxy, carboalkoxy andcarboxamide, including, but not limited to halonaphthyl, alkoxynaphthyland the like.

The term "alkylaryl" as used herein refers to a loweralkyl groupappended to an aryl radical.

The term "heterocyclic group" or "heterocyclic" as used herein refers toany 3- or 4-membered ring containing a heteroatom selected from oxygen,sulfur and nitrogen, or a 5- or 6-membered ring containing from one tothree nitrogen atoms; or one nitrogen and one oxygen atom; or onenitrogen and one sulfur atom; wherein the 5-membered ring has 0 to 2double bonds and the 6-membered ring has 0 to 3 double bonds; whereinthe nitrogen and sulfur heteroatoms may optionally be oxidized, whereinthe nitrogen heteroatom may optionally be quaternized, and including anybicyclic group in which any of the above heterocyclic rings is fused toa benzene ring.

Heterocyclics in which nitrogen is the heteroatom are preferred. Fullysaturated heterocyclics are also preferred. Preferred heterocyclics are:pyrryl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,imidazolyl, imidazolinyl, pyridyl, piperidinyl, pyrazinyl, piperazinyl,N-methylpiperazinyl, azetidinyl, N-methylazetidinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl,morpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl,indolyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzothiazolyl,benzoxazolyl, furyl, thienyl, triazolyl and benzothienyl.

Heterocyclics can be unsubstituted or monosubstituted or disubstitutedwith substituents independently selected from hydroxy, halo, oxo (═O),alkylimino (RN═wherein R* is a loweralkyl group), amino, alkylamino,dialkylamino, alkoxy, thioalkoxy, polyalkoxy, loweralkyl, haloalkyl orcycloalkyl.

The most preferred heterocyclics include imidazolyl, pyridyl,piperazinyl, N-methylpiperazinyl, azetidinyl, N-methylazetidinyl,thiazolyl, 2-aminothiazolyl, thienyl, triazolyl and the following:##STR31## wherein k is 1 or 2 and X is N, NH, O, or S, provided that Xis the point of connection only when X is N, ##STR32## wherein Y is NH,N-loweralkyl, O, S, or SO₂, or ##STR33## wherein the symbols (i), (ii)and (iii) represent 5-membered heterocycles containing one or moreheteroatoms and containing 2 double bonds; wherein Z₁ is N, O, or S andnot the point of connection and Z₂ is N when it is the point ofconnection and NH, O or S when it is not the point of connection; withthe proviso that when Z₂ is the point of connection, then Z₁ is N.

The term "N-protecting group" or "N-protected" as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures or to prevent the attack of exopeptidases onthe compounds. Commonly used N-protecting groups are disclosed inGreene, "Protective Groups in Organic Synthesis," (John Wiley & Sons,New York (1981)), which is hereby incorporated by reference.N-protecting groups comprise carbamates, amides, N-alkyl derivatives,amino acetal derivatives. In particular, N-protecting groups includeformyl, acetyl, benzoyl, pivaloyl, phenysulfonyl, benzyl,t-butyloxycarbonyl (Boc), benzyloxycarbonyl (Cbz) and the like.N-protecting groups also include an L- or D-aminoacyl residue, which mayitself by N-protected similarly.

The term "O-protecting group" as used herein refers to a substituentwhich protects hydroxyl groups against undesirable reactions duringsynthetic procedures such as those O-protecting groups disclosed inGreene, "Protective Groups in Organic Synthesis," (John Wiley & Sons,New York (1981)) and comprise substituted methyl ethers, for examplemethoxymethyl, benzyloxymethyl, 2-methoxyethoxymethyl,2-(trimethylsilyl)ethoxymethyl, benzyl and triphenylmethyl;tetrahydropyranyl ethers; substituted ethyl ethers, for example,2,2,2-trichloroethyl and t-butyl; silyl ethers, for example,trimethylsilyl, t-butyldimethylsilyl and t-butyldimethylsilyl; cyclicacetals and ketals, for example, methylene acetal, acetonide andbenzylidene acetal; cyclic ortho esters, for example, methoxymethylene;cyclic carbonates; cyclic boronates and the like.

The term "substituted amino" as used herein refers to:

I) alkylamino,

II) dialkylamino,

III) (hydroxyalkyl)(alkyl)amino,

IV) (dihydroxyalkyl)(alkyl)amino,

V) alkoxycarbonyalkylamino,

VI) carboxyalkylamino,

VII) (amino)carboxyalkylamino,

VIII) ((N-protected)amino)carboxyalkylamino,

IX) (alkylamino)carboxyalkylamino,

X) ((N-protected)alkylamino)carboxyalkylamino,

XI) (dialkylamino)carboxyalkylamino,

XII) (amino)alkoxycarbonylalkylamino,

XIII) ((N-protected)amino)alkoxycarbonylalkylamino,

XIV) (alkylamino)alkoxycarbonylalkylamino,

XV) ((N-protected)alkylamino)alkoxycarbonylalkylamino,

XVI) (dialkylamino)alkoxycarbonylalkylamino,

XVII) (alkoxyalkyl)(alkyl)amino,

XVIII)(alkoxyalkoxyalkyl)(alkyl)amino,

XIX) di-(alkoxyalkyl)amino,

XX) di-(alkoxyalkoxyalkyl)amino,

XXI) di-(hydroxyalkyl)amino,

XXII) ((unsubstituted heterocyclic)alkyl)(alkyl)amino,

XXIII) ((unsubstituted heterocyclic)alkyl)(alkyl)amino,

XXIV) ##STR34## wherein aa' is 1 to 5 and R_(6q) and R_(7q) areindependently selected from

1) hydrogen,

2) hydroxy,

3) alkoxy,

4) thialkoxy,

5) alkoxyalkoxy,

6) carboxy,

7) alkoxycarbonyl,

8) halogen,

9) amino,

10) alkylamino,

11) dialkylamino,

12) alkylsulfonylamino,

13) arylsulfonylamino,

14) alkylaminocarbonylamino,

15) alkylaminocarbonyloxy,

16) alkoxycarbonyloxy,

17) ##STR35## wherein dd' is 1 to 5, and 18) R_(8q) --Z_(q) -- whereinZ_(q) is O, S or NH and R_(8q) is a C₁ to C₆ straight or branched carbonchain substituted by a substituent selected from hydroxy, alkoxy,thioalkoxy, alkoxyalkoxy, amino, alkylamino, dialkylamino, carboxy,alkoxycarbonyl, aryl and heterocyclic;

XXV) ##STR36## wherein R_(9q) is 1) O,

2) S,

3) SO₂ or

4) C═O; or

XXXVI) ##STR37## wherein R_(10q) is 1) hydrogen,

2) loweralkyl,

3) an N-protecting group or

4) R_(11q) --C(O)-- wherein R_(11q) is aminoalkyl,(N-protected)aminoalkyl, 1-amino-2-phenylethyl or1-(N-protected)amino-2-phenylethyl.

The term "substituted methylene group" as used herein refers to:

--(I) --CHR_(13q) R_(14q) wherein

1) R_(13q) is

i) hydrogen or ii) hydroxy and

2) R_(14q) is

i) hydrogen,

ii) loweralkyl, iii) hydroxy,

iv) hydroxyalkyl, v) alkoxy,

vi) alkoxyalkyl, vii) azido,

vii) azidoalkyl, ix) amino,

x) (N-protected)amino,

xi) aminoalkyl,

xii) (N-protected)aminoalkyl,

xiii) alkylamino,

xiv) (N-protected)(alkyl)amino, xv) alkylaminoalkyl,

xvi) (N-protected)(alkyl)-aminoalkyl,

xvii) dialkylamino,

xviii) dialkylaminoalkyl,

xix) carboxyalkyl, xx) thioalkoxy,

xxi) thioalkoxyalkyl,

xxii) alkylsulfonyl,

xxiii)alkylsulfonylalkyl,

xxiv) thioaryloxy,

xxv) thioaryloxyalkyl,

xxvi) arylsulfonyl,

xxvii) arylsulfonylalkyl,

xxviii) (unsubstituted heterocyclic)alkyl or

xxvix) (substituted heterocyclic)alkyl such that when R_(13q) is hydroxythen R_(14q) is not hydroxy, alkoxy, azido, amino, alkylamino,dialkylamino, (N-protected)amino, (N-protected)(alkyl)amino, thioalkoxy,alkylsulfonyl or arylsulfonyl, and such that when R_(13q) is hydrogenthen R_(14q) is not hydrogen or loweralkyl;

(II) --C(═CH₂)C(O)NHR_(15q) ;

(III) --C(OH)(R_(16q))C(O)NHR_(15q) or

(IV) --CH(R_(16q))C(O)NHR_(15q) wherein

1) R_(15q) is

i) loweralkyl,

ii) hydroxyalkyl,

iii) alkoxyalkyl, iv) aminoalkyl,

v) alkylaminoalkyl,

vi) dialkylaminoalkyl,

vii) aryl,

viii) heterocyclic or

ix) (heterocyclic)alkyl and

2) R_(16q) is

i) hydrogen,

ii) loweralkyl,

iii) hydroxyalkyl, iv) haloalkyl or v) azidoalkyl;

(V) ##STR38## wherein 1) t' is 0 to 3,

2) R_(20q) is

i) CH₂ or

ii) N and

3) R_(21q) is

i) NH,

ii) O,

iii) S or

iv) SO₂,

such that when t' is 0 the R_(20q) is CH₂ and when t' is 1 to 3 thenR_(20q) is N,

(VI) --CH₂ CH(R_(22q))C(O)NHR_(23q) wherein

1) R_(22q) is

i) loweralkyl or ii) cycloalkyl

and

2) R_(23q) is

i) loweralkyl,

ii) hydroxyalkyl,

iii) alkoxyalkyl, iv) aminoalkyl,

v) alkylaminoalkyl,

vi) dialkylaminoalkyl,

vii) aryl,

viii) arylalkyl,

ix) heterocyclic,

x) heterocyclic)alkyl or

xi) ##STR39## wherein a) u' is 0 to 3,

b) R_(24q) is CH₂ or N and

c) R_(25q) is NH, O, S or SO₂,

such that when u' is 0 then R_(24q) is CH₂ and when u' is 1 to 3 thenR_(24q) is N;

(VII) ##STR40## wherein 1) R_(22q) is as defined above and

2) R_(74q) is

i) hydrogen,

ii) loweralkyl,

iii) an N-protecting group or

iv) R_(75q) --C(O)--wherein R_(75q) is aminoalkyl or(N-protected)aminoalkyl;

(VIII) ##STR41## wherein 1) R_(26q) is

i) loweralkyl or

ii) cycloalkylalkyl and

2) R_(27q) is

i) loweralkyl or

ii) cycloalkylalkyl;

(IX) --CH₂ CH(R_(81q))NHC(O)R_(82q) or --CH₂ CH(R_(81q))NHS(O)₂ R_(82q)wherein

1) R_(81q) is

i) loweralkyl or

ii) cycloalkylalkyl and

2) R_(82q) is

i) loweralkyl,

ii) alkoxy,

iii) alkylamino,

iv) dialkylamino,

v) --OR* wherein R* is aminoalkyl, alkylaminoalkyl, dialkylaminoalkyl or(heterocyclic)alkyl or

vi) ##STR42## wherein R_(21q) is as defined above; (X) --CH₂NCH(O)R_(82q) or --CH₂ NHS(O)₂ R_(82q) wherein R_(82q) is as definedabove; or

(XI) --CF₂ CH(OH)R_(83q) wherein R_(83q) is loweralkyl, loweralkenyl,cycloalkyl, cycloalkenyl, cycloalkylalkyl, cycloalkyenylalkyl, aryl,aryalkyl, heterocyclic or (heterocyclic)alkyl.

The terms "lipophilic or aromatic amino acid side chains" as used hereinrefer to amino acid side chains selected from the group isobutyl,isopropyl, sec-butyl, benzyl, p-methoxybenzyl, imidazole-4-yl-methyl,p-hydroxybenzyl, 1- and 2-naphthylmethyl, (pyrazolyl)methyl,(thiazolyl)methyl, cyclohexylmethyl, (3-indolyl)methyl, CH₃ SCH₂ -- andthe like. General references to amino acid side chains in both thedescription and claims herein is to be taken as reference to such,whether naturally occurring in proteins or not, and to both D- andL-forms.

The terms "Ala", "His", "Leu", "Phe", "Tyr", "Cys", "Gly", "Lys", "Sar","Pro", "HomoPhe" and "norLeu" as used herein refer to alanine,histidine, leucine, phenylalanine, tyrosine, cysteine, glycine, lysine,sarcosine, proline, homophenylalanine and norleucine, respectively. Ingeneral, the amino acid abbreviations follow the IUPAC-IUB JointCommission on Biochemical Nomenclature for amino acids and peptides(Eur. J. Biochem. 1984, 158, 9-31).

Renin inhibitors having one asymmetric carbon atom can exist as theracemic mixture or as pure enantiometers. Renin inhibitors having two ormore asymmetric carbon atoms can exist as pure diastereomers, mixturesof diastereomers, diastereomeric racemates or mixtures of diastereomericracemates. The present invention includes within its scope all of theisomeric forms. The term "S" and "R" configuration as used herein are asdefined by the IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-30.

Renin inhibitors having the general structure shown in group (9) can beprepared as described in Fung, et al., PCT Patent Application WO90/03971(PCT/US89/04385), published Apr. 19, 1990, which is hereby incorporatedby reference. The syntheses of segments containing substituents D aredescribed in the Examples or have previously been described (Kempf, etal., J. Med. Chem. 1987, 30, 1978; Luly, et al., J. Med. Chem. 1987, 30,1609; Buhlmayer, et al., U.S. Pat. No. 4,727,060; Morisawa, et al.,European Patent Application No. 0228192; Ten Brink, PCT PatentApplication No. W087/02986).

Renin inhibitors having the generally structure shown in group (10) canbe prepared as described in De, et al., PCT Patent Application No.WO90/04917 (PCT/US89/04649), published May 17, 1990, which is herebyincorporated by reference. The syntheses of segments containingsubstituents R₅ are described in the Examples or have previously beendescribed (Kempf, et al., J. Med. Chem. 1987, 30, 1978; Luly, et al., J.Med Chem. 1987, 30, 1609; Buhlmayer, et al., U.S. Pat. No. 4,727,060;Morisawa, et al., European Patent Application No. 0228192; Ten Brink,PCT Patent Application No. W087/02986).

An intermediate useful in the preparation of certain renin inhibitors iscompound 8 (Scheme I). Scheme I outlines a process for the preparationof 8. D-Isoascorbic acid (I) can be converted to the known lactol 3 (J.Am. Chem. Soc. 105 3661 (1983)). Reaction with 2-isopropylidenetriphenylphosphorane provides alcohol 4. Oxidation to aldehyde 5,followed sequentially by reaction with benzylamine andcyclohexylmagnesium bromide/CeCl₃, provides amine 7. Deprotection of theamino group, reduction of the olefin and removal of the acetonideprotecting group provides 8.

An alternative preparation of the reduced form of compounds 5 (i.e., 13)is shown in Scheme II. Epoxyalcohol 10 (J. Am. Chem. Soc. 109 1525(1987)) can be protected and then reacted with isopropyl grignard toprovide 11. Reaction with camphorsulfonic acid (CSA), followed byozonolysis, gives the aldehyde 13. ##STR43##

Another intermediate useful in the preparation of certain renininhibitors is compound 21 (Scheme III). Reaction of aldehyde 14 withn-butyl magnesium bromide, followed by oxidative resolution, provides 15as a single enantiomer. Reaction of the alcohol 15 with bromoaceticacid, optionally followed by esterification provides 16 or 17.Alteratively, reaction with t-butyl bromoacetate provides 18. Alkylationwith benzylbromide provides a mixture of 19 and the desired 20, whichcan be separated from the mixture. Hydrogenolysis or hydrolysis of theester, coupling with 4-methoxymethoxypiperidine and oxidation providesthe desired carboxylic acid 21. ##STR44##

The following examples will serve to further illustrate preparation ofthe compounds of the invention,

EXAMPLE 12(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanoicacid amide of3-(4-morpholinyl)propyl-5(S)-amino-6-cyclohexyl-4(S)-hydroxy2(S)-isopropylhexanamideExample 1A:4(S)-t-Butyloxycarbonylamino-5-cyclohexyl-3(R,S)-hydroxy-1-pentene

To a stirred -78° C. solution of Boc-cyclohexylalanine methyl ester(10.2 g, 35.8 mmol) in dry toluene (60 ml) was added diisobutylaluminumhydride (34 ml of a 1.5 M solution in toluene). After 30 min, vinylmagnesium bromide (108 ml of 1 M solution in tetrahydrofuran (THF)) wasadded. After stirring for 15 h at 0° C., the mixture was carefullyquenched with methanol, treated with Rochelle salts (22 ml of saturatedaqueous solution in 140 ml H₂ O), and filtered. After extracting thesolids 5 times with ethyl acetate, the extracts and filtrate werecombined and the organic phase was washed with brine, dried, filteredand evaporated to an oil (10.2 g). Chromatography on silica gel elutingwith hexane/ethyl acetate mixtures provided 6.1 g of the desiredproduct. Anal. calcd. for C₁₆ H₂₉ NO₃ .1/4 H₂ O: C, 66.8; H, 10.3; N,4.9. Found: C, 66.9; H, 10.2; N, 4.7.

Example 1B:3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyl-5-vinyloxazolidine.

The procedure of S. Thaisrivong (J. Med. Chem. 1987, 30, 976) wasemployed. A solution of 40 g of the resultant compound of Example 1A and102 g of 2-methoxypropene in 250 ml of dichloromethane was stirred atroom temperature. Solid pyridinium p-toluenesulfonate (PPTS) (177 g wasadded slowly to the reaction mixture. After addition was complete, thereaction was stirred for 1 h and neutralized by addition of solid sodiumbicarbonate. The solids were filtered and the filtrate was concentrated.Flash chromatography on silica gel gave 57 g of the desired compound.IR(CDCI₃) 1690 (C═O carbamate)cm⁻¹ ; ¹ HNMR (CDCI₃) 5.95 (m,IH), 5.32(m,IH), 5.20 (dt,IH), 4.27 (dd,IH), 1.47 (s,9H).

Anal. Calcd. for C₁₉ H₃₃ NO₃ C, 70.55; H, 10.28;

N, 4.33.

Found: C, 70.47; H, 10.27; N, 4.09.

Example 1C:3-(t-Butyloxycarbonyl)-4-(cyclohexylmethyl)-2,2-dimethyloxazolidine-5-carboxaldehyde.

A solution of 10 g of the resultant compound of Example 1B in 150 ml of2:1 dichloromethane; methanol was cooled in an dry-ice acetone bath.Ozone was bubbled through the solution until a blue color persisted (1h). Dry nitrogen was then bubbled through the reaction mixture to removeexcess dissolved ozone. The reaction mixture was cannulated into asuspension of 8 g zinc dust, 8 ml glacial acetic acid, 200 ml water, and200 ml of methanol cooled to -45° C. After 5 min the bath was removedand the mixture allowed to warm to room temperature overnight. 100 ml ofsaturated sodium chloride was added and the entire reaction mixtureextracted with two 300 ml portions of dichloromethane. The combineddichloromethane extracts were decanted, dried (MgSO₄), filtered, andevaporated. The crude aldehyde was purified by flash chromatography(1:4) ethyl acetate:hexane to give 9.7 g of the desired compound as amixture of diastereomers (3:1 trans:cis) as judged by the integratedresonances of the two aldehyde protons. IR(CDCI 3) 1735 (C═) aldehyde),1690 (C═O carbamate)cm⁻¹ ; ¹ HNMR (CDCI₃ 9.83 (s, 1H,CHO), 9.73(d,IH,CHO cis diastereomer), 4.14 (m,IH), 1.46 (s,9H).

Anal. Calcd. for C₁₈ H₃₁ NO₄ C, 66.43; H, 9.60; N, 4.30.

Found: C, 65.27; H, 9.79; N, 4.20.

Equilibriation of Aldehyde Isomers

A suspension of 25 g of the above aldehyde in 300 ml of methanol andpowdered potassium carbonate (10.7 g) was stirred at room temperaturefor 6 h. The reaction mixture was cooled in an ice-water bath andtreated with 9.3 g of glacial acetic acid for 5 min. A solution of 0.5 Msodium dihydrogen phosphate (300 ml) was added to the mixture. After 30min, the solution was concentrated to one-half the volume under reducedpressure and extracted with ether (600 ml). The combined ether extractswere dried (M_(g) SO₄), filtered, and concentrated. The aldehyde waspurified by flash chromatography using (1:4) ethyl acetate:hexane togive 19.5 g of the desired compound as an 8:1 mixture of trans:cisdiastereomers.

Example 1D:3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2dimethyl-4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-3-hydroxy-2(R)-isopropyl-1-oxopropyl)-4(R)-methyl-5(S)-phenyl-2-oxazolidinone.

The title compound was prepared in analogy to the procedure of S.Thaisrivongs, D.T. Pals, L. T. Kroll, S. R. Turner and F. S. Han, J.Med. Chem. 1987, 30, 976-82, from the resultant compound of Example 1C,in 63% yield. M. p. 97° C. ¹ HNMR (CDC1₃) 0.91 (d, 3H), 1.06 (d, 3H),1,1 (d, 3H), 1.48 (s, 9H), 0.9-1.9 (several bm, 12 H total), 2.12 (bd,1H), 2.3 (m, 1H), 3.81 (dd, 1H), 3.94 (td, 1H), 4.04 (bm, 1H,) 4.22 (dd,1H), 4.84 (dq, 1H), 5.61 (d, 1H), 7.31-7.45 (m, 5H). High resolutionmass spectrum. Calcd. for (M+H)+Of C₃₃ H₅₁ N₂ O₇ : 587.3698. Found:587.3696.

Analysis. Calcd. for C₃₃ H₅₀ N₂ O₇ : C, 67.55; H, 8.59;

N, 4.77. Found: C, 67.41; H, 8.61; N, 4.77.

Example 1E:3-(3(R)-(3-(tert-Butyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(R)-oxazolidinyl)-3-((1-imidazolyl)thionyloxy)-2(R)-isopropyl-1-oxopropyl)-4(R)-methyl-5(S)-phenyl-2-oxazolidinone.

The resultant compound from Example 1D (1,840 g, 3,136 mmol) and1,1'-thiocarbonyldiimidazolide (1.128 g, 6.330 mmol) were refluxed in 8mL dry 1,2-dichloroethane under a nitrogen atmosphere for 24 h. Themixture was concentrated and the residue purified by flashchromatography (2.5% MeOH--CH₂ Cl₂) to afford 1,896 g (87%) of the titlecompound. ¹ H NMR(CDCI₃) 0.93 (d, 3H),1.04 (d, 3H), 1.08 (d,3H), 1.5(bs, 9H), 0.9 -1.9 (several bm, 13H total), 2.05 (m, 1H), 4.13 (bm, 1H),4.23 (dd, 1H), 4.81 (dd, 1H), 4.94 (dq, 1H), 5.70 (d, 1H), 6.33 (dd,IH),7.06 (bs, 1H), 7.3-7.5 (m, 5H), 7.61 (bs, 1H), 8.40 (bs, 1 H). Highresolution mass spectrum. Calcd. for (M+H)+of C₃₇ H₅₃ N₄ O₇ S: 697.3635.Found: 697:3629. Analysis. Calcd. for C₃₇ H₅₂ N₄ O₇ S: C, 63.77; H,7.52; N, 8.04. Found: C, 63.58; H, 7.44; N, 7.94.

Example 1F: 3-(3-(3-(tertButyloxycarbonyl)2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)-2(R)-isopropyl-1-oxopropyl)-4(R)-methyl-5(S)-phenyl-2-oxazolidinone,

A solution of the resultant product from Example 1E (6.50 g, 9.33 mmol)in 275 ml of dry toluene was degassed with argon for 30 min. then warmedto reflux (under argon). A solution of tri-n-butyltin hydride (5.43 g,18.6 mmol) in 75 ml of dry, degassed toluene was added dropwise over 15min. After an additional 2 h of reflux, the reaction was cooled,concentrated and purified by flash chromatography (5% EtOAc-hexanes) toafford 4.82 g (90%) of the title compound as a white foam. ¹ HNMR(CDC1₃) 0.90 (d, 3H), 0.92 (d, 3H), 0.9-1.1 (bm, 3H), 1.06 (d, 3H),1.15 -1.35 (bm, 3H), 1.51 (s, 9H), 1.57-2.14 (several bm, 16H total),3.84 (m, 1H), 3.97 (m, 1H), 4.85 (dq, 1H), b 5.68 (d, 1H), 7.3-7.46 (m,5H). Mass spectrum: (M+H)+=571.

Analysis. Calcd. for C₃₃ H₅₀ N₂ O₆ : C, 69.44; H, 8.83;

N, 4.91. Found: C, 69.31; H, 8.82; N, 4.89.

Example 1G:2(S)-((3-(tert-Butyloxycarbonyl-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)methyl)-3-methylbutanoic acid.

Using the procedure of D. A. Evans, T. C. Britton and J. A. Ellman,Tetrahedron Lett. 1987, 28(49), 6141-44, the resultant product fromExample 1F (6.10 g, 10.7 mmol) was hydrolyzed with aq. LIOH and hydrogenperoxide in THF. The crude material was purified by flash chromatography(15% EtOAc-0.5% HOAc-hexanes) to provide 3.53 g (90%) of the titlecompound as a viscous colorless oil. ¹ H NMR(CDC1₃) 0.96 (d, 3H), 1.00(d, 3H), 1.1-1.3 (bm, 5H), 1.48 (s, 9H), 1.5-1.9 (several bm, 15Htotal), 2.0 (m, 1H), 2.66 (m, 1H), 3.7 (bm, 1H), 3.90 (m, 1H). Massspectrum: (M+H)+=412.

Analysis. Calcd. for C₂₃ H₄₁ NO₅.0.25 H₂ O: C, 66.39;

H, 10.05; N, 3.37. Found: C, 66.46; H, 9,84; N, 3.36.

Example 1H: 3-(4-Morpholinyl)propyl2(S)-((3-tertbutyloxycarbonyl)-2,2-dimethyl-4(S)-cyclohexylmethyl-5(S)-oxazolidinyl)methyl)-3-methylbutanamide.

The procedure of P. Buhlmayer, et. al., J. Med. Chem. 1988, 31(9),1839-46 was adapted. The resultant compound from Example 1G (75 mg,0.182 mmol), HOBT (42.0 mg, 0.274 mmol) and N-methylmorpholine (55 mg,0.55 mmol) were dissolved in 1.0 ml dry DMF, and the solution was cooledto -20° C. (under nitrogen). EDAC (53 mg, 0.28 mmol) was added as asolid, and the resulting mixture was stirred at -20 to 0° C. for 1 h.The mixture was sealed, and allowed to react at 0° C. (in refrigerator)for 48 h. To the resulting solution was added4-(3-aminopropyl)morpholine (0.23 mmol). The resulting solution wasstirred at 0° C. for 4 h, and for a further 20 h, allowing it to warmslowly to room temperature. The volatiles were removed by high vacuumdistillation, and the residue was partitioned between CH.sub. 2 Cl₂ andaq. NaHCO₃. The aqueous phase was extracted 3X with CH₂ Cl₂, and thecombined organic phases were washed with brine, dried (Na₂ SO₄) andconcentrated. Purification by flash chromatography (4% MeOH-CH₂ CI₂)provided the desired compound.

¹ H NMR(CDCI₃) 0.92 (d, 3H), 0.95 (d, 3H), 1.46 (s) and 1.48 (s, 12Htotal), 1.57 (bs, 3H), 0.8-1.8 (several bm, 18H total), 2.01 (m, 1H),2.46 (bm, 6H), 3.37 (m, 2H) 3.64 (bm, 1H), 3.75 (bm, 5H), 6.80 (bt, 1H).High resolution mass spectrum. Calcd. for (M+H)+ of C₃₀ H₅₆ N₃ O₅ :538.4220. Found: 538.4220.

Example 1I:1(S)-(4-(Methoxymethoxyl)piperidin-1-yl-carbonyl)-2-phenylethanol.

A solution of 176 g (1.3 mol) of 1hydroxybenzotriazole (Aldrich), 80 g(0.48 mol) of L-3-phenyllactic acid (prepared from L-phenylalanine), 76g (0.52 mol) of 4-(methoxymethoxy)piperidine in 800 mL of DMF was cooledto -25° C. (internal temperature) while 132 g EDC HCI (Saber Labs) wasadded mechanical stirring). After addition, the reaction was stirred tort over 24 h. Excess DMF was removed under high vacuum and the residuedissolved into 1.5 L of ethyl acetate. The ethyl acetate solution waswashed with 4 L of saturated sodium bicarbonate. The ethyl acetate layerwas separated, dried (MgSO₄) and evaporated to give approximately 138 gof crude amide. The product was isolated by silica gel chromatographyusing ethyl acetate/hexane as eluant. Yield 120 g (79%).

¹ H NMR(CDCI₃, TMS) 1.61 (m,2H), 1.81 (m,2H), 2.89 (m,2H), 3.38 (s,3H),3.5 (m,2H), 3.79 (m,2H), 3.96 (m,1H), 4.62 (t,1H), 4.68 (s,2H).

Example 1J:2(S)-(1)(S)-(4-(Methoxymethoxy)piperidin-1-yl-carbonyl)-2-phenylethoxy)hexanoicacid.

The resultant compound of Example 1I (1.45 g, 4.95 mmol), in 10 ml THFwas added dropwise to the cooled suspension of sodium hydride (60%dispersion in oil, 0.5 g, 11.2 mmol) in 4 ml THF (0-5° C.). Thesuspension was stirred for 20 mins at 0-5° C. and then warmed up to roomtemperature and stirred for additional 1 h. Solution ofD-2-bromohexanoic acid in 6 ml THF was added dropwise to the cooledsuspension (0-5° C.) under N₂ atmosphere. It was then allowed to warm upto room temperature and stirred overnight, quenched with cold H₂ O andextracted with ethylacetate to remove undesired starting material. Itwas acidified with 1 M sodium hydrogen sulfate and extracted withchloroform. After filtration and evaporation, the crude product waspurified on silica gel, eluted with CH₂ CI₂ : CH₃ OH:A_(c) OH(19.4:0.3:0.3to obtain 0.79 g of desired acid (43% yield).

¹ H NMR(CDCI₃, TMS) 0.88 (t,3H), 3.35 (s,3H), 3.98 (bt,IH), 4.6 (m,IH),4.64 (s,2H), 7.38 (m,5H). Mass spectrum: (M+H)+=408.

Example 1K:2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-ylcarbonyl-2-phenyl)ethoxyhexanoicacid amide of 3-(4-morpholinyl)propyl5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.

The resultant compound from Example 1H (0.161 mmol) was deprotected bydissolving in 1.0 ml dry CH₂ Cl₂, cooling the solution to -10° C. (undernitrogen), and treating with 1.0 ml of trifluoroacetic acid. Theresulting solution was stirred at -10 to 0° C. for 4 h. The solventswere largely removed with a stream of nitrogen, and the residue (as aconcentrated solution in trifluoracetic acid) was dissolved in 1.0 mlTHF and 0.3 ml water at 0° C. The solution was allowed to warm slowly toambient temperature over 18 h. The crude aminoalcohol was isolated bybasifying the reaction with an excess of 1.0 M aq. Na₂ CO₃, saturatingthe solution with NaCl, and extracting with 5×10 ml of 5% EtOH-CHCl₃.The combined organic phases were washed with brine, dried (Na₂ SO₄),concentrated, and the residue placed under high vacuum overnight toyield 66.2 mg (100%) of yellow viscous oil.

Coupling was achieved by combining the resultant compound from Example1J (72 mg, 0.177 mmol), the above aminoalcohol (0.168 mmol), HOBT (34mg, 0.22 mmol) and N-methylmorpholine (25 mg, 0.25 mmol) in 1.0 ml dryDMF. The resulting solution was cooled to -20° C. (under argon), andEDAC (45 mg, 0.23 mmol) was added. The reaction was allowed to slowlywarm to room temperature as the ice bath melted, for a total of 24 h.The solvent was removed by high vacuum distillation, and the residue waspartitioned between 15 ml CH₂ Cl₂, 9 ml sat. aq. NaHCO₃ and 1 ml H₂ O.The aqueous phase was further extracted (3×10 ml CH_(Cl) ₂), and thecombined organic phases where washed with 10 ml brine, dried (Na₂ SO₄)and concentrated. Purification by flash chromatography yielded the titlecompound as a hygroscopic glassy solid, m.p. 49-51° C. ¹ H NMR(CDCl₃)0.90 (m), 0.91 (d) and 0.92 (d, 9H total), 0.65-1.90 (several bm,approx. 28H total), 2.02 (m, 1H), 2.45 (bm, 6H), 2.95 (m, 1H, 3.05 (dd,1H), 3.20 (bm, 2H), 3.36 (s, 3H) 3.45 (m, 2H), 3.6-4.0 (several bm) and3.71 (m, 10H total), 4.48 (dd, 1H), 4.68 (s, 2H), 5.80 (d) and 5.88 (d,1H total), 6,87 (bt, IH), 7.3 (bm, 5H). Mass spectrum: (M+H)+=787.

Example 22(S)-(1(S)-(4-Methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanoicacid amide of 3-(4-morpholinyl)propyl-5(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide(Alternate Preparation) Example 2A 2(S)-Cyclohexylalanine methyl ester,hydrochloride salt

L-Phenylalanine (215 g, 1.3 mole) was hydrogenated over Pd/C in HOAc,filtered and concentrated. The resulting cyclohexylalanine was taken upin MeOH (1200 mL). Thionyl chloride (427 g, 3.59 mole) was slowly addedto the slurry, which eventually became homogeneous. The reaction wascooled in an ice/water bath and addition of thionyl chloride wascontinued. The reaction mixture was heated to reflux for 2h, cooled andconcentrated to afford a solid, which was taken up in ether andfiltered. The white solid was washed with ether in the filter funnel anddried in vacuo to give 271 g of product, 94% yield over two steps. m.p.150-150° C.

Example 2B 2(S)-N-(Triphenylmethyl)cyclohexylalanine methyl ester

Cyclohexylalanine methyl ester, HCI salt (88 g, 398 mmol) was taken upin chloroform (40 ML). Triethylamine (b 84.6 g, 836 mmol) was then addedin one portion to the slurry and stirred five minutes.Triphenylmethylchloride (111 g, 398 mmol) was then added, and thereaction was stirred for 5h at ambient temperature. The internaltemperature of the reaction reached 50° C., however, external coolingwas not employed. The reaction mixture was washed with 1M KHSO₄ solution(2×100 mL), saturated NaHCO₃ (200 mL), brine (100 mL), then dried overMgSO₄. The solution was then concentrated to give 200 g of residue whichwas filtered through 900-1000 g of silica gel (elution gradienthexane-10:1 hexane: ethyl acetate) affording 157 g of product (93%),which could be crystallized from hexanes: ethyl acetate to afford largewhite crystals. m.p. 86-87° C.

Example 2C Dimethyl 3(S)-4-Cyclohexyl-(N-triphenylmethyl)amino-2-oxobutylphosphonate

To a -78° C. solution of dimethyl methylphosphonate (272.5 g, 2.2 mol)in 1.6L THF was added n-BuLi (2.5 M, 800 mL, 2.0 mmol) and stirred 45minutes. The product of Example 2B (156 g, 366 mmol) in 40 mL THF wasthen added dropwise. This reaction mixture was stirred at -50° C. for 3h, then at -40° C. for 6h then finally warmed to ambient temperatureovernight. The reaction mixture was concentrated, taken up in ether,washed with 1M KHSO₄, saturated NaHCO₃ (twice) and brine, dried andconcentrated. The residue (200 g) was filtered through 1000 g silicagel, (1.1 hexanes:ethyl acetate) to give 135 g of beta-keto phosphate(72%) as an oil.

Example 2D6(S)-7-Cyclohexyl-2-methyl-6-(N-triphenylmethyl)-amino-5-oxohept-2-ene-3-oicacid

The product of Example 2C (117.2 g, 229 mol) was dissolved in 600 ml THFand cooled to 0° C. To this solution was added hexanes washed NaH (60%,9.6 g(wet), 240 mmol) and the mixture was stirred 30 min. Next was addedmethyl 3-methyl-2-oxobutyrate (29.8 g, 229 mmol) in 100 ml THF andstirred at 0° C. for 4 h. Volatiles were removed at reduced pressure,the residue was dissolved in 1:1 hexanes: ether (500 ml) and washed withwater (100 ml), NaHCO₃ (200 ml), brine (200 ml), dried (MgSO₄) andconcentrated to afford 129 g of the desired ester as an oil. Thismaterial (123 g) was taken up in 460 ml THF, 229 ml MeOH, cooled to 0°C. then 18.86 g of LiOH-H₂ O in 229 ml of distilled water was added.This solution was allowed to warm to room temperature and stirred for 3days. Volatiles were removed at reduced pressure and the resultingaqueous solution was washed with ether (100 ml×2) then acidified to pH 3with 6N HCI. The aqueous solution was then extracted with EtOAc (300ml×2), washed with brine, dried (MgSO₄) and concentrated to give 116 gof a yellow foam. This material was recrystallized from 525 ml of hothexanes/EtOAc (12/1) to give 72.4 g of a white solid (62% for threesteps). m.p. 97-98° C.

Example 2E(5S,6S)-6-Cyclohexylmethyl-3-isopropylidene-5-hydroxypiperidine-2one

A solution of 3.06 g (6.0 mmol) of the product of Example 2D in 50 mlTHF was added to 6.8 g (60 mmol) of N-hydroxysuccinimide. Thishomogeneous solution was cooled to 0° C., then DCC (1.25 g, 12 mmol) in5 ml THF was added. The cooling bath was removed and the reaction wasstirred for 2H. At this time, an additional 1.25 g of DCC was added.After 5H of total reaction time, the mixture was filtered. concentratedand dissolved in either. The organics were washed with NaHCO₃ (aq, 50ml×2), brine, dried (MgSO₄) and concentrated at reduced pressure to give5.2 g of product as an oil, which was dissolved in 20 ml ether. A 1Nsolution of HCI/Ether (30 ml) was added. A gummy solid immediatelyprecipitated out of solution; CH₂ Cl₂ (25 ml) was added and the clearreaction mixture was stirred overnight. After 12 h, the product whichprecipitated from the mixture was collected by filtration and washedwith ether to give, after drying, 2.1 g of a white solid in 87% yieldfor two steps, which was taken on in the following step.

To a 0° C. slurry of the above-mentioned white solid resulting from thefirst part of Example 2E (1.2 g, 3.0 mmol) in 20 ml CH₂ Cl₂ was addedimidazole (24 mg, 3.0 mmol). The resulting reaction mixture was stirredfor 1 h, then washed with 20 ml of KHSO₄, water, saturated NaHCO₃, andbrine. The organic portion was dried over MgSO₄, filtered and cooled to-78° C. To the cold solution was added L-Selectride® (Aldrich, 1.0 M,5.0 ml, 5.0 mmol) and stirred for 10 min. The reaction mixture was thenwarmed to -40 ° C. and quenched with 20% citric acid solution. Theorganics were washed with 20 ml of water, saturated NaHCO₃ solution,brine, dried over MgSO₄, and concentrated to afford a clear oil. Thisresidue was purified on silica gel (50% hexanes/ethyl acetate) to givean oil which was triturated with ether to afford a white solid, 545 mg,72% yield from active ester, m.p. 128-130° C.

Example 2F (2S,4S,5S)-5-Amino-6-cyclohexyl-2-isopropyl-4-hexanolide

A solution of the product of Example 2E (24.7 g, 98.4 mmol) in 500 ml ofethyl acetate was treated with 2.5 g of dry Pd/C and hydrogenated at 4atm for 4h at ambient temperature. The reaction mixture was filtered andconcentrated to a white foamy solid which was taken on without furtherpurification.

The resulting saturated lactam was dissolved in 200 ml of 6N HCI and 50ml of ethanol then heated to reflux for 14h. The reaction mixture wasconcentrated at reduced pressure and azeotropically dried with tolueneto afford a pale oil This material was taken up in water and extractedwith hexane, then made basic by addition of a solution of NaHCO₃.Extraction with ethyl acetate followed by drying (MgSO₄) and removal ofvolatiles afforded a yellowish oil which solidified to a white solidupon standing. Recrystallization from hexane gave 20.7 g (90%) ofproduct as white needles. m.p. 49-50° C.

Example 2G2(S)-(1(S)-(4-Methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanoicacid amide of3-(4-morpholinyl)propyl-5(S)-amino-6cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide

The product of Example 2F was reacted withN-(benzyloxycarbonyloxy)succinimide to provide the N-Cbz protected aminolactone. Reaction of the N-Cbz protected amino lactone with3-amino-1-(morpholin-4-yl)propane provided 3-(4-morpholinyl)propyl5(S)-benzyloxycarbonylamino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide.This product can be N-deprotected and coupled with the product ofExample 1J according to the procedure of Example 1K to provide thedesired compound.

Example 3(2S)-2-Benzyl-3-(1-methylpiperazin-4-ylsulfonyl)propionyl-(L)-(4-Thiazolyl)AlaAmide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptaneExample 3A Methyl 3-Hydroxy-2-methylene-3-phenylpropionate

A mixture of benzaldehyde (82.1 mL, 0.81 mol), methyl acrylate (109.1mL, 1,211 mol), 1,4- diazabicyclo(2,2,2)octane (13.6 g, 0.12 mol), andacetic acid (1.4 mL, 0.024 mol) was allowed to stir at 35° C. for 60 h,at which point the reaction was determined to have proceeded to 70%completion by ¹ H NMR. Methyl acrylate (20.9 mL, 0.23 mol) was thenadded and the solution was allowed to react at 35° C. for an additional48 h. The mixture was diluted with diethyl ether (1.0 L) and was washedwith 2×200 mL portions of a pH 7 phosphate buffer. After concentrationin vacuo, the remaining mixture was distilled at reduced pressure (12mm) to afford 6.5 g of unreacted benzaldehyde and 130.0 g (90%) of thedesired product as a colorless oil: b.p. 130° C. (12 mm); IR (film)1718, 1440 cm⁻¹ ; ¹ H NMR (CDCI₃) delta 3.67 (s, 3H), 5.52 (br s, 1H),5.83-5.85 (m, 1H), 6.29-6.31 (m, 1H), 7.23-7.39 (m, 5H); ¹³ C NMR (75MHz, CDCl₃) delta 51.8, 72.9, 125.8, 126.5, 127.7, 128.3, 141.2, 141.9,166.6.

Example 3B (Z)-1-Bromo-2-carboxymethoxy-3-phenyl-2-propene

To a 2 L, 3-neck Morton flask fitted with a thermometer, a mechanicalstirrer, and an addition funnel was added the resultant compound fromExample 3A (305.9 g, 1.585 mol) followed by addition of 48% HBr (505 mL,4.46 mol) in one portion. The flask was immersed in an ice-water bath,at which time concentrated sulfuric acid (460 mL, 8.62 mol) was addeddropwise over 90 min and the internal temperature of the reactionmixture was maintained at 23-27° C. throughout the addition process.After removal of the ice-water bath, the mixture was allowed to stir atambient temperature overnight. The solution was then transferred to aseparatory funnel and the organic layer was allowed to separate from theacid layer. The acids were drained and the organic layer was dilutedwith 2 L of a 1:1 ethyl acetate/hexane solution, washed with saturatedaqueous sodium bicarbonate solution (1 L), dried over sodium sulfate,and concentrated to yield 400 g (99%) of the desired product as a lightyellow oil, which was used without any additional purification: b.p.180° C. (12 mm); IR (film) 1718, 712 cm⁻¹ ; ¹ H NMR (CDC1₃) delta 3.89(s, 3H), 4.40 (s, 2H), 7.38-7.45 (M, 3H), 7.56-7.60 (m, 2H), 7.83 (s,1H); ¹³ C NMR (75 MHz, CDCl₃)delta 26.77, 52.47, 128.63, 128.87, 129.61,134.20, 142.95, 166.62.

Example 3C (Z)-2-Carbomethoxy-3-phenyl-2-propene-1-sulfonic Acid SodiumSalt

To a 12 L, 3-neck round bottom flask fitted with a mechanical stirrerthermometer and an addition funnel was added the resultant product fromExample 3B (400 g, 1.57 mol) and methanol (4 L). The mixture was warmedto 50° C. and a solution of sodium sulfite (199 g, 1.57 mol) dissolvedin water (4 L) was added over 75 min while the internal temperature ofthe flask was maintained at 50° C. After the addition was complete, theclear solution was allowed to stir at 50° C. for an additional 45 min.The reaction mixture in solution was taken to the next step withoutadditional purification. The compound can be isolated by concentrationto an amorphous powder, which is contaminated with an equivalent ofsodium bromide: IR (KBr) 1711, 1628, 1215 cm⁻¹ ; ¹ H NMR (DMSO D-6)delta 3.70 (s, 3H), 3.77 (s, 2H), 7.33-7.41 (m, 3H), 7.48 (s, 1H),7.87-7.89 (m, 2H); ¹³ C NMR (75 MHz, DMSO D-6) delta 49.88, 51.93,127.36, 128.33, 128.91, 129.82, 134.75, 139.06, 168.60.

Example 3D 2-Carbomethoxy-3-phenylpropane-1-sulfonic Acid Sodium

To the 8 L of 1:1 methanol/water mixture containing the resultantcompound from Example 3C was added 60 g of W-24 raney nickel. Theresulting suspension was pressurized under 50 psi of hydrogen and wasallowed to shake on a Parr shaker for 24 h, at which time an additional20 g of raney nickel catalyst was added. After 6 h under 50 psi ofhydrogen, the catalyst was removed by filtration and the solution wasconcentrated to dryness. To the dry white solid was added ethyl acetate(6 L) and heptane (4 L) and the solution was vigorously stirred with amechanical stirrer overnight. The white suspension was removed byfiltration yielding 530 g (88%) of the desired product as an amorphouspowder that was contaminated with approximately one equivalent of NaBr.The compound was used without any additional purification: IR (KBr)1740, 1215, 1050 cm⁻¹. ¹ H NMR (DMSO D-6) delta 2.48-2.54 (m, 1H), 2.74-2.87 (m, 2H), 2.91-3.04 (m, 2H), 3.48 (s, 3H), 7.12-7.32 (m, 5H); ¹³ CNMR (75 MHz, D₂ O/DMSO D-6) delta 38.18, 44.80, 52.67, 52.82, 127.42,129.13, 129.34, 138.14, 176.84.

Example 3E 2-Carboxymethoxy-3-phenyl-1-propanesulfonyl Chloride

To a 3 L round bottom flask was added the resultant compound fromexample 3D (530 g, 1.39 mol) and toluene (520 mL) followed by theaddition of PCI₅ (317 g, 1.52 mol). The mixture was warmed to 50° C.with stirring for 45 mn. It was then diluted with toluene (1 L) and wasfiltered through celite. After concentration in vacuo, 371 g (96%) ofthe desired product was obtained as a light brown oil: IR (film); 1740,1380, 1170 cm⁻¹ ; ¹ H NMR (CDC1₃); delta 2.92 (dd, 1H, J=8.1, 14.0),3.17 (d, 1H, J =6.6, 14.0), 3.41-3.50 (m, 1H), 3.67 (dd, 1H, J=3.3,14.3), 3.72 (s, 3H), 4.20 (dd, 1H, J=8.8, 14.3), 7.15-7.18 (m, 2H),7.25-7.35 (m, 3H); ⁻⁻ C NMR (75 MHz, CDC1₃) delta 37.26, 42.88, 52.65,64.89, 127.49, 128.87, 128.92, 135.61, 171.79.

Example 3F Methyl2-Benzyl-3-(1-methyl-piperazin-4-ylsulfonyl)proprionate

To a 1 L round bottom flask was added the resultant compound fromExample 3E (84.5 g, 0.305 mol) and dichloromethane (305 mL). The mixturewas cooled to 0° C. in an ice water bath and a solution of N-methylpiperazine (35.5 mL, 32.1 g) dissolved in dichloromethane (305 mL) wasadded dropwise with vigorous stirring over 90 min. After the additionwas completed, the ice-water bath was removed and the mixture wasstirred an additional 4 h while warming to ambient temperature. Thesolution was then poured into a separatory funnel containing 1 L of a 5%aqueous NaOH solution. The layers were partitioned and the organic layerwas dried over potassium carbonate. Concentration in vacuo yielded anoil, which was filtered through 200 g of silica gel using 4:1hexane/ethyl acetate as an eluant. Concentration gave 84.3 g (81%) ofthe desired product as a yellow oil: IR (film); 1735, 1165, 955 cm⁻¹ ; ¹H NMR (CDC1₃) delta 2.30 (s, 3H), 2.42 (t, 4H, J=4.8), 2.88 (dd, 1H,J=7.7, 14.0), 2.93 (dd, 1H, J=3.7, 14.0), 3.06 (dd, 1H, J=7.0, 13.6),3.18-3.27 (m, 5H), 3.43 (dd, 1H, J=8.82, 13.9), 3.67 (s, 3H), 7.14-7.17(m, 2H), 7.24-7.34 (m, 3H); ¹³ C NMR (75 MHz, CDC1₃) delta 37.91, 42.22,45.36, 45.83, 49.61, 52.21, 54.36, 127.06, 128.66, 128.92, 129.06,136.79, 173.33.

Example 3G (2S) 2-Benzyl-3-(4-methyl-piperazin-1-yisulfonyl)propionicAcid

The resultant racemic ester from Example 3F (135 g, 397 mmol) wassuspended in acetone (300 mL) and water (900 mL). While being stirredvigorously at a temperature of 35° C., a crude preparation of SubtilisinCarlsberg (10 mL, Alcalase 2.4L, Novo Laboratories) was added. Sodiumhydroxide solution (6 M) was used to maintain the reaction at pH7.5-8.0. After 3 days, the acetone was removed under reduced pressureand the aqueous phase was extracted with CHCl₃ (1 L) to remove theunreacted ester. The aqueous phase was adjusted to pH 7 with 3 M HCI andwas desalted by eluting through a column of Amberlite XAD-16(2 kg,prewashed sequentially with water, methanol, and water) using a water towater/methanol gradient. Evaporation of the solvent afforded 46 g (70%)of a white solid: mp 184.5° C.; TLC (25% ethyl acetate/25% water/25%acetic acid/25% n-butanol)R_(f) =0.43; anal. (C₁₅ H₂₂ N₂ O₄ S0.25 H₂ O)

Calcd: C, 54.44; H, 6.85; N, 8.47.

Found: C, 54.77; H, 6.53; N, 8.39.

Example 3H Diethyl (2-Bromoallyl)acetamidomalonate

To a stirred mixture of diethyl acetaminomalonate (217 g, 1.0 mol) and2,3-dibromopropene (240 g, 1.2 mol) in dry tetrahydrofuran (2.50 L),under nitrogen, was added sodium hydride (26.4 g, 1.1 mol) in severalportions. The reaction mixture was stirred at room temperature for 30min, then heated to reflux. After heating for 18 h, the resultant slurrywas cooled to room temperature and suction filtered through a short padof silica gel. The solid rescue as washed with tetrahydrofuran (2×50mL), and the filtrates were combined and concentrated. The residue wasdissolved in ethyl acetate (2.0 L), washed with water and brine, andthen was dried over MgSO₄. Filtration and concentration gave a yellowoil which solidified upon drying. The resultant solid was recrystallizedfrom a mixture of hot ethyl acetate/hexane to give 301 g (89%) of thedesired product: m.p. 85-87° C.

Example 3I Diethyl (3-Bromo-2-oxo-propyl)acetamidomalonate

To a cold (0° C.), stirred solution of the resultant compound fromExample 3H (280 g, 0.83 mol) in a mixture of 2:1 acetonitrile/water(1.68 L) was added solid N-bromosuccinimide (193 g, 1.08 mol) in threeportions over a period of b 15 min. The resultant orange mixture wasstirred at 0° C. for an additional period of 1 h and then was allowed towarm to room temperature. After 4 h, the reaction mixture was treatedwith 10% aqueous sodium thiosulfate, diluted with ethyl acetate, andwashed sequentially with water, 10% aqueous NaHSO₄ (3×), water, andbrine. Drying (MgSO₄) and concentration afforded a yellow solid whichwas crystallized from a mixture of ethyl acetate and hexane to give 247g (85%) of the desired compound as a white solid: m.p. 97-98.5° C.

Example 3J Diethyl (4-Thiazolylmethyl)acetamidomalonate

A 5 L, 3-neck round bottom flask equipped with a mechanical stirrer,stopper and a drying tube was charged with the resultant compound fromExample 3I (325 g, 0.92 mol) and flushed with nitrogen. A freshlyprepared solution of thioformamide in tetrahydrofuran (0.8 M, 1.25 L)was added in one portion. The reaction mixture was stirred at roomtemperature for 4 h. The resultant slurry was then diluted with ether(1.25L) and cooled to 0° C. The solid was then collected by suctionfiltration and washed with cold ether (3×) to give the title compound asthe hydrochloride salt. This material was transferred to a 4 Lseparatory funel, slurried with ethyl acetate (2 L) and basified by thecareful addition of 2 M NaOH. The organic layer was separated, washedwith water and brine, and then dried over MgSO₄. Filtration andconcentration afforded a pale yellow oil which solidified upon drying togive 242 g of the desired compound. This material was recrystallizedfrom an ethyl acetate/hexane mixture to afford 185.6 g (64%) of purematerial: m.p. 104-106° C.

Example 3K N-Acetyl-3-(4-thiazolyl)-DL-alanine Ethyl Ester

To a stirred solution of the resultant compound from Example 3J (185.6g, 0.59 mol) in a mixture of tetrahydrofuran (620 mL) and ethanol (310mL) was added aqueous 2 M LiOH (325 mL, 0.65 mol) dropwise over 20 min.After stirring at room temperature for 2.5 h, the reaction mixture wasconcentrated and the resultant aqueous mixture was extracted with ether(3×200 mL), adjusted to pH 3 with 3 M HCI, and concentrated underreduced pressure. Residual water was removed by evaporating portions oftoluene (2×200 mL). The residue was diluted with toluene (1.5 L) and theresultant slurry was heated to reflux with separation of water(Dean-Stark trap). After 3 h the reaction mixture was cooled to roomtemperature, diluted with ethyl acetate (1.5 L) and suction filteredthrough SiO₂ (60 g). The solids were washed with additional ethylacetate (4×500 mL) and the combined organics were concentrated to afforda pale yellow oil which solidified on drying (0.5 torr) to afford 119.6g (84%) of the desired compound: m.p. 58-62° C.

Example 3L N-Acetyl-3-(4-thiazolyl)-L-alanine andN-Acetyl-3-(4-thiazolyl)-D-alanine Ethyl Ester

A 5 L, 3-neck round bottom flask equipped with a mechanical stirrer wascharged with the resultant compound from Example 3K (210 g, 0.87 mol),distilled water (1.6 L), and 1 M aqueous KCI (0.8 L). The homogeneoussolution was adjusted to pH 7.0 with 0.1 M NaOH and then was treatedwith Subtilisin Carlsberg (1.8 g) dissolved in 0.1 M aqueous KCI (25mL). The reaction mixture was stirred at room temperature with 1.0 MNaOH added as required to maintain the pH at 6.25 -7.25. After 4 h, 430mL of base had been consumed and the reaction was judged to be complete.The reaction mixture was then extracted with chloroform (4×1.5 L), theaqueous phase was carefully acidified to pH 4 with 2 M HCL and then wasconcentrated under reduced pressure. Residual water was removed byconsecutive evaporation of portions of toluene (3×500 mL) and ethanol(3×500 mL). The residue was taken up in warm ethanol (3×400 mL). Theresidue was taken up in warm ethanol and suction filtered to removeinorganic salts. The solids were washed with warm ethanol (3×400 mL) andthe filtrates were concentrated to afford 92.6 g (50%) ofN-acetyl-3-(4-thiazolyl)-L-alanine as a white solid: m.p. 186° C.

The combined chloroform fractions from the extractions were washed withsaturated aqueous NaHCO₃, water, and brine and then were dried overMgSO₄. Filtration and concentration gave 103 g (49%) ofN-acetyl-3-(4-thiazolyl)-D-alanine ethyl ester. This material could befurther purified by recrystallization from ethyl acetate/hexane: m.p.79-80° C.

Example 3M Epimerization of N-Acetyl-3-(4-thiazolyl)-D-alanine EthylEster

A 2 L round bottom flask equipped with a magnetic stirrer, refluxcondenser and nitrogen inlet was charged with sodium (0.96 g, 0.045 mol)and ethanol (900 mL) and the mixture was allowed to reflux until thesodium was consumed. The resultant solution of sodium ethoxide wascooled slightly, and N-acetyl-3-(4-thiazolyl)-D-alanine ethyl ester fromExample 3L (102 g, 0.42 mol) was added. The reaction mixture was thenheated to reflux. After 3 h the solution was cooled to room temperature,quenched with glacial acetic acid (0.045 mol) and concentrated to removeethanol. The residue was diluted with ethyl acetate, washed with waterand brine and dried over MgSO₄. Filtration and concentration gave ayellow oil which was purified by recrystallizing from a mixture of hotethyl acetate and hexane to yield 89 g (87%) of material identical tothat obtained from Example 3L.

Example 3N 3-(4-Thiazolyl)-L-alanine Dihydrochloride

A 2 L round bottom flask equipped with a magnetic stirrer was chargedwith N-acetyl-3-(4-thialzoyl)-L-alanine from Example 3L (92.6 g, 0.43mol) and 6 M HCI (1 L). The resultant solution was heated to reflux.After 3 h the mixture was allowed to cool to room temperature. Thesolution was then concentrated under reduced pressure, evaporated fromtoluene (3×200 mL), and dried under vacuum overnight to give 120 g of aslightly wet solid. This material was used in the next reaction withoutfurther purification.

Example 3O N-Boc-3-(4-thiazolyl)-L-alanine

A 4 L Erlenmeyer flask equipped with a mechanical stirrer was chargedwith the resultant compound from Example 3N (125.9 g) andtetrahydrofuran (1.5 L) and the mixture was adjusted to pH 6.6 withsaturated aqueous sodium bicarbonate. The resultant solution was thenadjusted to pH 8.9 with 3.0 M NaOH and a solution ofdi-tert-butyldicarbonate (117.8 g, 0.51 mol) in tetrahydrofuran (150 mL)was added. The reaction mixture was vigorously stirred at roomtemperature for 40 h. The tetrahydrofuran was removed under vacuum, thepH of the residue was adjusted to 2.0 with 3.0 M HCI and the mixture wasextracted with ethyl acetate (3×300 mL). The combined extracts weredried over MgSO₄, filtered, and concentrated to give 150 g of a whitesolid. Recrystallization from hot 1:1 ethyl/hexane (1.06 L) gave 107.6g(82% form the resultant compound of Example 3M) of the desired compoundm.p. 115° C.; [alpha]_(D) =+129.8 (c=1.04, CHCl₃).

Anal. (C₁₁ H₁₆ N₂ O₂).

Calcd: C, 48.53; H, 5.88; N, 10.29.

Found: C, 48.58; H, 5.91; N, 10.17.

Example 3P Boc-L-(4-Thiazolyl)Ala Amide of (2S, 3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

(2S,3R,4S)-2-"(tert-Butyloxycarbonyl)amino]-1-cyclohexyl-3,4-dihydroxy-6-methylheptane(5.05 g, 14.7 mmol, Luly et al., J. Org. Chem. 1988, 53, 6109) wasstirred for 90 min in 4 M HCI in ethanol and then evaporated Ether wasadded and evaporated 3 times and the residue was dried under highvacuum. To this residue was added 1-hydroxybenzotriazole (5.57 g, 41.2mmol), the resultant acid from Example 30 (4.00 g, 14.7 mmol),dimethylformamide (60 mL) and N-methylmorpholine (3.40 mL, 30.9 mmol).The mixture was cooled to -23° C., treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (4.03 g,21.0 mmol). After 2 h at -23° C. and 21 h at ambient temperature themixture was poured into saturated NaHCO₃ solution and extracted intoethyl acetate. The organic layer was washed with water and brine, thendried over Na₂ SO₄ and evaporated to a white solid which wasrecrystallized from 1.15 (v/v) methylene chloride/ether (multiple crops)affording 6.28 g (86%) of the desired product as a flaky white solid:m.p. 159-160° C.; TLC (15% CH₃ OH/85% CHCl₃) R_(f) =0.63; ¹ H NMR(CDC1₃) delta 8.78 (1H,d), 7.14 (1H, d), 6.18 (2H, br d), 4.44 (1H, dd),4.27 (1H, m), 4.10 (1H, m), 3.37 (1H, dd), 3.30-3.12 (3H,m), 1.89 (1H,septet), 1.46 (9H, s), 0.94 (3H, d), 0.88 (3H, d).

Anal. (C₂₅ H₄₃ N₃ O₅ S).

Calcd: C, 60.33; H, 8.71; N, 8.44.

Found: C, 60.43; H, 8.68; N, 8.51.

Example 3Q H-L-(4-Thiazolyl)Ala Amide of(2S,3R,4S)-2Amino-1-cyclohexy-3,4-dihydroxy-6-methylheptane

Trifluoroacetic acid (50 mL) was slowly added via cannula to a solutionof the resultant compound from Example 3P (6.27 g, 12.6 mmol) inmethylene chloride (50 mL) at 0° C. The reaction was stirred 3h at 0° C.and concentrated in vacuo (40° C. bath) to an oil which was basified topH 10-11 with aqueous K₂ CO₃. The product was extracted into chloroform,dried over Na₂ SO₄, filtered, and concentrated to a foam.Recrystallization from 1:4 (v/v) methylene chloride/hexane gave 5.00 g(100%) of the desired product as a fluffy white solid: m.p. 111-112° C.;TLC (15% CH₃ OH/85% CHCl₃) R_(f) =0.46; ¹ H NMR (CDCl₃) delta 8.77 (1H,d), 7.40 (1H, br d), 7.13 (1H, d), 4.54 (1H, m), 4.25 (1H, m), 3.80 (1H,dd), 3.33 (1H, dd), 3.25-3.12 (3H, m), 0.95 (3H, d), 0.86 (3H, d).

Anal (C₂₀ H₃₅ N₃ O₃ S)

Calcd: C, 60.42; H, 8.87; N, 10.57.

Found: C, 60.05; H, 8.65; N, 10.42.

Example 3R(2S)-2-Benzyl-2-(4-methylpiperazin-1-ylsulfonyl)propionyl-(L)-(4-Thiazolyl)AlaAmide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

To the resultant acid from Example 3G (1000 g, 3.064 mmol), theresultant amine from Example 3Q (1.110 g, 2.792 mmol), and1-hydroxybenzotriazole (1.022 g, 7.563 mmol) in dimethylformamide (20mL) was added N-methylmorpholine (0.35 mL, 3.2 mmol). The mixture wascooled to -23° C. and treated with1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (0.760 g,3.96 mmol). After 2 h at -23° C. and 14 h at ambient temperature, thereaction was poured into saturated NaHCO₃ solution (100 mL) andextracted into ethyl acetate (2×50 mL) which was washed with water (2×50mL) and brine (50 mL) and then was dried over Na₂ SO₄ and evaporated toafford 1.94 g. Recrystallization from ethanol (15 mL)/hexane (90 mL)afforded 1.559 g (79%) of a white solid: m.p. 169-170° C.; TLC (10% CH₃OH/90% CHCl₃) R_(f) =0.40; ¹ H NMR (CDCl₃) delta 8.73 (1H, d), 7.43 (1H,d), 7.37-7.16 (6H, m), 6.23 (1H, d), 4.63 (1H, dd), 2.30 (3H, s), 0.95(3H, d), 0.87 (3H, d).

Anal. (C₃₅ H₅₅ N₅ O₆ S₂ 0.75 H₂ O)

Calcd: C, 58.43; H, 7.91; N, 9.73

Found: C, 58.51; H, 7.74; N, 9.60.

Example 4 Alternative Preparation of N-Boc-3-(4-thiazolyl)-L-alanineExample 4A Ethyl (2-Bromoallyl)acetamidoacetate

To a solution of the product of Example 3H (3.36 g, 10.0 mmol) indimethylformamide (10 mL) was added sodium chloride (586 mg, 10.0 mmol),water (360 microliters, 20 mmol) and 4N hydrochloride acid in dioxane(0.012 mL, 0.5 mmol). The reaction vessel was Firestone purged threetimes and placed under a positive nitrogen pressure. The reactionmixture was heated at reflux for 24 hours and then concentrated invacuo. The residue obtained was diluted with water (5 mL) and extractedwith ether (3×15 mL). The combined organic extracts were decolorizedwith charcoal (0.5 g), dried over magnesium sulfate, filtered, andconcentrated in vacuo to afford the title product (2.51 g, 95%) as apale yellow oil. ¹ H NMR (300 MHz, CDCl₃) 1.29 (t, 3H), 2.04 (s, 3H),2.99 (m, 2H), 4.22 (q, 2H), 4.79 (m, 1H), 5.53 (d, 1H), 5.68 (m, 1H),6.44 (d, 1H); IR (film) 1195, 1220, 1370, 1540, 1660, 1740, 2990, 3050,and 3300 cm⁻¹. MS (DCI/NH₃) m/e 264/266 (M+H)⁺, 281/283 (M+H+NH3)⁺.Anal. Calcd. for C₉ H₁₄ NO₃ Br: C, 40.92; H, 5.34; N, 5.30. Found: C,42.04; N, 5.48; N, 5.26.

Example 4B N-Boc-(2-Bromoallyl)glycine

A slurry of the product of Example 4A in 0.1 N potassium chloridesolution (300 mL) containing 0.2 M pH 7.0 phosphate buffer (30 mL) wastreated with a solution of Subtilisin Carlsberg (4 mg) in 0.1 Npotassium chloride solution (3 mL). The pH was maintained between 6.50and 7.25 by addition of 2.0 N sodium hydroxide solution via a pH-Stat.After 25 minutes, the rate of hydrolysis noticeably slowed; and theunreacted D-ester was extracted with methylene chloride (3×150 mL).

The resulting aqueous phase was treated with cobalt(II) acetate (6 mg)and Acylase I (80 mg). The reaction mixture was stirred for 4 hours anddetermined to be complete.

The pH of the reaction mixture was adjusted to 10 by the addition ofsolid sodium carbonate. The resulting solution was treated withd-tert-butyl dicarbonate (6.55 g, 30 mmol) dissolved in THF (100 mL) andvigorously stirred for 16 hours. The aqueous solution was washed withhexane (200 mL) to remove any unreacted protecting-reagant. The aqueouslayer was adjusted to pH 2.5 by the addition of solid potassium hydrogensulfate and extracted with ethyl acetate (2×200 mL). The combinedorganic layers were washed with brine (100 mL), dried over magnesiumsulfate, and concentrated in vacuo to give the title compound (7.30 g,81%) as a pale yellow crystalline solid.[alpha]_(D) at 25° C.=-9.86°(MeOH), c=1.085. ¹ H NMR (300 MHz, CDCl₃) 1.48 (s, 9H), 2.91 (m, 2H),4.52 (m, 1H), 5.19 (d, 0.5H), 5.53 (m, 1H), 5.71 (s, 1H), 6.79 (d,0.5H), 11.3 (s, 1H); IR (CDCl₃) 1150, 1250, 1400, 1500, 1620, 1640,1710, 3000, 3350, and 3520 cm⁻¹. (DCI/NH₃) m/e 311/313 (M+H+NH₃)⁺. Anal.Calcd. for C₁₀ H₁₆ NO₄ Br: C, 42.12; H, 5.66; N, 4.91. Found: C, 41.38;H, 5.59; N, 4.75.

Example 4C (2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic acid

To a solution of the product of Example 4B (2.00 g, 6.80 mmol) in water(30 mL) and tetrahydrofuran (15 mL) cooled to 0° C. was addedN-bromosuccinimide (1.45 g, 8.16 mmol) in three portions over twentyminutes. After the addition was complete, the ice bath was removed andthe solution was stirred for four hours. The tetrahydrofuran was removedin vacuo and the product was extracted with ethyl acetate (3×35 mL). Theorganic extracts were combined and washed with 5% sodium chloridesolution (25 mL) and brine (25 mL), dried over magnesium sulfate, andconcentrated in vacuo to afford the title compound (1.70 g, 81). ¹ H NMR(300 MHz, CDCl₃) 1.45 (s, 9H), 3.30 (m, 2H), 3.93 (s, 2H), 4.61 (m, 1H),5.51 (d, IH). MS (DCI/NH₃) m/e 310/312 (M+H)⁺, 327/329 (M+H+NH₃)⁺.

Example 4D (2R)-N-Boc-2-Amino-3-(4-thiazolyl)propanoic Acid

To the solution of the product of Example 4C (91 mg, 0.293 mmol) intetrahydrofuran (5 mL) was added thioformamide (17.7 mg, 0.29 mmol).[Thioformamide was prepared by reacting a slight excess of phosphoruspentasulfide with formamide in tetrahydrofuran. The resulting solutionwas diluted with hexanes and filtered through a silica gel plug andstored at -25° C.⃡ The resulting solution was allowed to stand forsixteen hours and then concentrated in vacuo to afford a residue whichwas partitioned between diethyl ether and aqueous sodium bicarbonate.The aqueous layer was washed with ether (2×10 mL) and methylene chloride(10 mL), adjusted to pH 2.3 with solid potassium hydrogen sulfate, andextracted with ether (3 ×20 mL). The combined organic extracts weredried over magnesium sulfate and concentrated in vacuo to afford thetitle compound as a white crystalline solid (55 mg, 71%). ¹ H NMR (300MHz, CDCl₃) 1.48 (s, 9H), 3.48 (m, 2H), 4.52 (m, 1H), 5.61 (m, 1H), 7.18(d, 1H), 8.91 (d, 1H).

Example 5 Alternative Preparation of(2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic acic Example 5A Diethyl(2-Chloroallyl)acetamidomalonate

To a suspension of 95% sodium hydride (17.2 g, 680 mmol) intetrahydrofun (1.2 L) was added 2,3-dichloropropene (100 g, 900 mmol),diethylacetamidiomalonate (146 g, 672 mmol) and tetrabutylammoniumbromide (6.00 g). The resulting thick suspension was warmed at refluxunder nitrogen for 20 hours. The reaction mixture was concentrated invacuo and the resulting residue was partitioned between water (200 mL)and a mixture of ether (300 mL) and methylene chloride (100 mL). Theorganic phase was washed with 5% sodium chloride solution (200 mL) andbrine (200 mL), dried over magnesium sulfate, filtered, and concentratedin vacuo. The resulting solid (195 g) was dissolved in hot hexanes (1300mL) and allowed to cool to room temperature and sit overnight to affordthe title compound as a crystalline solid (157 g, 80%). mp 76.3° C. ¹ HNMR (300 MHz, CDCl₃) 1.29 (t, 6H), 2.05 (s, 3H), 3.48 (s, 2H), 4.28 (m,4H), 5.18 (m, 1H), 5.29 (m, 1H), 6.92 (bs, 1H); IR (CDCl₃) 1140, 1180,1200, 1240, 1270, 1300, 1500, 1630, 1680, 1740, 2950, 2990, and 3300cm⁻¹. MS (DCI/NH₃) m/e 292/294 (M+H)⁺, 309/311 (M+H+NH₃)⁺. Anal. Calcd.for C₁₂ H₁₈ NO_(Cl:) C, 49.41; H, 6.22; N, 4.80. Found: C, 49.18; H,6.29; N, 4.75.

Example 5B Ethyl(2-Chloroallyl)acetamidoacetate

The product of Example 5A (137 g, 500 mmol) was hydrolyzed anddecarboxylated by the procedure described in Example 4A to afford thetitle compound (105.4 g, 96%) as a pale yellow oil which crystallizedupon standing. ¹ H NMR (300 MHz, CDCl₃) 1.31 (t, 3H), 2.05 (s, 3H), 2.79(m, 2H), 4.22 (q, 2H), 4.79 (m, 1H), 5.23 (m, 1H), 5.29 (m, 1H), 6.61(m, 1H); IR 1200, 1220, 1280, 1300, 1370, 1440, 1550, 1638, 1659, 1740,2890, 2990, 3050, and 3300 cm⁻¹. MS (DCI/NH₃) m/e 220/222 (M+H)⁺,237/239 (M+H+NH₃)⁺. Anal. Calcd. for C₉ H₁₄ NO₃ Cl: C, 49.21; H, 6.42;N, 6.38. Found: C, 46.58; H, 6.05; N, 6.02.

Example 5C (2R)-N-Boc-2-Amino-5-bromo-4-oxopentanoic acid

The product of Example 5B is treated according to the procedure ofExamples 4B and 4C to provide the desired product.

Example 6 Alternative Preparation of2(S)2-Benzyl-3-(4-methyl-piperazin-1-ylsulfonyl) propionic acid Example6A 2-Carbomethoxy-3-phenylpropane-1-sulfonic acid Sodium salt

To a 0.3M ethanolic solution of the product of Example 3B,(Z)-1-bromo-2-carbomethoxy-3-phenyl-2-propene, (0.98 molar equivalents)was added over one hour at 50° C. at 1.4M aqueous solution of sodiumsulfite (1.0 molar equivalent). The mixture was stirred for 10 hours at50° C., and then the ethanol was removed under reduced pressure at 50°C. Ethyl acetate (3 kg per 1 kg of bromide) was added and the mixturestirred for an additional 15 minutes and let stand for 10 minutes. Thelayers were separated and the aqueous layer was washed as above with twoadditional aliquots of ethyl acetate (1 kg per 1 kg of bromide).

Raney nickel (1 kg per 10 kg of aqueous solution) was added to theaqueous solution which was then evacuated and purged with nitrogenfollowed by hydrogen (3×) and placed under 40 psi of hydrogen for 6.5 to9.5 hours. The Raney nickel was removed by filtration using nitrogenpressure, and the filtrate was concentrated under reduced pressure at55° C. A 10% aqueous acetone solution (0.3 kg per 1 kg of startingbromide) was added to the residue obtained, and the mixture was warmedat 50° C. for 30 minutes. Additional acetone (3 kg per 1 kg of startingbromide) was slowly added over one hour to effect crystallization of theproduct. After stirring for one hour, the product was removed byfiltration and washed with acetone to afford the title compound in60-65%. m.p. 255° C. dec. The 300 MHz ¹ H NMR spectrum was found to beconsistent with the proposed structure. A second crop was obtained byaddition additional acetone (2.5 kg per 1 kg of starting bromide) andcooling to -20° C. for 10-12 hours and removing the second crop byfiltration. An additional 13-40% yield of title compound was obtained inthat way.

Example 6B Methyl 2-Benzyl-3-(4-methyl-piperazin-1-ylsulfonyl)propionate

The product of Example 6A (1 molar equivalent) was mixed with phosphoruspentachloride (1.5 molar equivalents) and warmed at 70-75° C. for 3-4hours. The reaction mixture was cooled to room temperature and thendiluted with toluene (16.7 molar equivalents) and added to 10% aqueoussodium chloride solution (4 kg per 1 kg of phosphorus pentachloride)while maintaining the temperature below 40° C. The mixture was stirredfor 5 minutes, allowed to settle for 15 minutes, and then the phaseswere separated. The sodium chloride wash was repeated as describedabove. The toluene phase was cooled to 5° C. and N-methylpiperazine (3molar equivalents in 3 molar equivalents of toluene) was addedmaintaining the temperature below 15° C. The mixture was stirred for 4-6hours and then washed with 8% aqueous sodium hydroxide (2×3.4 kg per 1kg of phosphorus pentachloride). The combined basic washes werere-extracted with toluene (0.25 kg per 1 kg of sodium hydroxidesolution). The combined toluene extracts were washed with water (1 kgper 1 kg of phosphorus pentachloride), and the toluene was removed bydistillation at reduced pressure to afford the title compound (65-70%)as a viscous oil which crystallized on standing. The 300 MHz ¹ H NMRspectrum was found to be consistent with the proposed structure. MS(DCI/NH₃) m/e 341 (M+H)⁺ .

Example 6C (2S)-2-Benzyl-3-(4-methylpiperazin-1-yl sulfonyl)propionicAcid

The product of Example 6B (69 kg, 20 mol) in acetone (420 kg)/water (960kg) was adjusted to pH 8.0 using 1N sodium hydroxide. Alcalase ™(Subtilisin) was added and the pH was maintained between 7.9 and 8.4 bythe addition of 1N sodium hydroxide. When 80% of the theoretical amountof sodium hydroxide had been consumed, the reaction was quenched by theaddition of ethyl acetate. The reaction mixture was concentrated to halfthe original volume under reduced pressure and then washed with ethylacetate (2 ×700 kg). The volume of the aqueous phase was concentrated byhalf and the pH adjusted to 5.2. The reaction mixture was treated withXAD-16 resin (50 kg), stirred for 18 hours, and applied to an XAD-16resin column (50 kg). The column was eluted with water (500 kg) and then35% ethanol in water (1000 kg) to afford a residue which was treatedwith isopropanol (270 kg) and warmed to 75° C. Upon cooling to roomtemperature and subsequently to -5° C., crystalline material wasobtained. The solid was removed by filtration, washed with coldisopropanol (30 kg) and dried at 50° C. to afford the title compound (13kg, 49%). The 30 MHz ¹ H NMR spectrum was found to be consistent withthe proposed structure. MS (DCI/NH₃) m/e 327 (M+H)⁺. This compound couldbe recrystallized from 1:1 isopropanol/water.

Example 7 Alternative Preparation of2(S)-2-Benzyl-3-(4-methylpiperazin-1-ylsulfonyl)propionyl-L-(4-thiazolyl)Ala Amide of (2S, 3R, 4S)-2-Amino-1-Cyclohexyl-3,4-dihydroxy-6-methylheptane Example 7A(2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6 -methylheptane

A 3.5% solution of2S-Boc-amino-1-cyclohexyl-3R,4S-dihydroxy-6-methylheptane in 4Nhydrochloric acid gas in anhydrous ethanol was prepared at 0-5° C. After4 hours at 0-5° C., nitrogen was bubbled through the reaction mixture toremove dissolved hydrochloric acid gas. The solvent was removed underreduced pressure at 50° C. to afford a solid which was dissolved inethyl acetate and water. Potassium carbonate was added to bring the pHof the mixture to between 10 and 11, and the layers were separated. Theaqueous layer was extracted with additional portions of ethyl acetate.The combined organic extracts were washed with water and brine, driedover magnesium sulfate, and concentrated under reduced pressure at 50°C. to afford a solid. The solid was crystallized by dissolving in aminimum amount of ethanol at 40° C. and then water was slowly addeduntil the ratio of ethanol to water was 40/60 (w/w). The solution wascooled to 0-5° C. at a rate of 5° C. per hour. The cooled mixture wasstirred for not less than 2 hours prior to removal of the solid byfiltration. The solid was dried in a vacuum oven at 45° C. until a losson drying was less than 0.1%. The title compound was obtained as a whitecrystalline solid in 65-72%. m.p. 106-108° C. The 300 MHz ¹ H NMRspectrum was found to be consistent with the proposed structure. MS(DCI/NH₃) m/e 244 (M+H)⁺.

Example 7B Boc-L-(4-Thiazolyl)-Ala Amide of(2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

To a solution of the product of Example 7A (14.25 g, 58.5 mmol),N-Boc-L-(4-Thiazolyl)Alanine (17.45 g, 64.4 mmol), and1-hydroxybenzotriazole hydrate (HOBT) (9.86 g, 64.4 mmol) dissolved indimethylformamide (DMF) (33 mL) and cooled to 0-5°0 C. in an ice bathwas added dropwise over 30 minutes, a solution of1,3-dicyclohexylcarbodiimide (DCC) (14.5 g, 70.3 mmol) dissolved in DMF(27 mL).

After one hour, the reaction mixture was allowed to warm to roomtemperature and stirred for 24 hours. The reaction was quenched by theaddition of citric acid (1.14 g, 6.0 mmol) and ethanol (1.31 mL, 1.05 g,22.0 mmol). The mixture was stirred for 1 hour and then ethyl acetatewas added (285 mL). After an additional 30 minutes, the solid by-productwas removed by filtration and washed with ethyl acetate (48 mL).Additional ethyl acetate (1.9 L) was added and the organic phase waswashed with 1% sodium chloride (713 mL), 5% citric acid containing 1%sodium chloride (2×713 mL, 8% sodium bicarbonate (2×713 mL) and 20%sodium chloride (2×713 mL) and concentrated under reduced pressure toafford an off-white solid. The solid was dissolved in isopropanol (200mL) with warming, treated with decolorizing carbon at 50° C. for onehour, and filtered through Celite. The filtrate was diluted withisopropanol (50 mL) and stirred at room temperature with a mechanicalstirrer for 15 hours. The solid suspension was cooled to 0-5° C. with anice bath and stirred at this temperature for 3 hours. The solid wasremoved by cold filtration, washed with cold 1:1 isopropanol/heptane(100 mL), and dried in a vacuum oven at 50° C. for 48 hours to affordthe title compound as a white solid in 85% yield. m.p. 156-158° C. The300 MHz ¹ H NMR spectrum was found to be consistent with the proposedstructure. MS (DCI/NH₃) m/e 498 (M+H)⁺.

Example 7C H-L-(4-Thiazolyl)Ala Amide of(2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

A 12% solution of the product of Example 7B at 15-25° C. in 3Nhydrochloric acid was prepared. After 4 hours at 15-25° C., the reactionmixture was quenched by pouring it into a mixture of 4% sodiumchloride/ethyl acetate. The pH of the mixture was brought up to 10-12 bythe addition of 10% sodium hydroxide. The layers were separated and theaqueous layer extracted with ethyl acetate (2×). The combined organicextracts were washed with 25% sodium chloride (2×), dried over magnesiumsulfate, treated with activated carbon at 50° C. for 1 hour, andfiltered through Celite. The filtrate was concentrated to a solid underreduced pressure at 45° C. The solid was crystallized by dissolving in aminimum amount of ethyl acetate (5× by weight) and triturating withheptane until the ratio of ethyl acetate to heptane was 30/70 (w/w). Thesolution was cooled to 0-5° C. and stirred for two hours and thenfiltered. The solid was dried in a vacuum oven at 45° C. for 60 hours oruntil the loss on drying was less than 0.1%. The title compound wasobtained as a white crystalline solid in 70-82%. yield. m.p. 109-112° C.The 300 MHz ¹ H NMR spectrum was found to be consistent with theproposed structure. MS (DCI/NH₃) m/e 398 (M+H)⁺.

Example 7D (2S)-2-Benzyl-3-(4-methylpiperazin-1-yl sulfonyl)propionyl-L-(4-Thiazolyl) Ala Amide of(2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The product of Example 7C (3.00 g, 7.6 mmol), the product of Example 6C,2S-benzyl-3(4-methyl-piperazin-1-yl sulfonyl) propionic acid, (2.59 g,7.0 mmol), and HOBT (1.27 g, 8.3 mmol) were dissolved in DMF (30 mL).After stirring at room temperature for 1 hour, the reaction mixture wascooled to 0-5° C. in an ice bath and treated with the dropwise additionover a 30 minute period of a solution of DCC (1.72 g, 8.3 mmol)dissolved in DMF (8 mL). After 1 hour, the reaction mixture was allowedto warm to ambient temperature and stirred for 24 hours. The reactionmixture was quenched with citric acid (0.15 g, 0.26 mmol) and ethanol(0.17 mL, 3.04 mmol) and stirred for 1 hour. Ethyl acetate (60 mL) wasadded and the mixture was stirred for an additional hour. The by-productwas removed by filtration and washed with ethyl acetate (10 mL). Thefiltrate was diluted with ethyl acetate (400 mL) and washed with 5%sodium bicarbonate solution (2×100 mL). The solvent was removed underreduced pressure to afford an off-white solid. The solid was dissolvedin isopropanol (80 mL) with warming, treated with decolorizing carbon at55° C. for 1 hour, filtered through Celite, and stirred at ambienttemperature with a mechanical stirrer for 12 hours. The white solidsuspension was cooled to 0-5° C. in an ice bath for 3 hours and filteredcold. The solid obtained was washed with cold 1:1 heptane/isopropanol(25 mL) and dried in a vacuum oven at 55° C. for 48 hours to afford thetitle compound (4.32 g, 81%) as a white solid. m.p. 169-170° C. The 300MHz ¹ H NMR spectrum was found to be consistent with the proposedstructure. MS (DCI/NH₃) m/e 706 (M+H)⁺.

Example 8N-(4-Morpholinylsulfonyl)-(L)-Phenylalanyl-(L)-(2-amino-4-thiazolyl)AlanylAmide of (2S,3R,4S)-2-Amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane

The title compound can be prepared according to the procedure disclosedin European Patent Application No. EP 399556, published Nov. 28, 1990.

The ability of a renin inhibitor invention to treat psoriasis isdemonstrated as follows. A 62-year-old woman patient with documentedpsoriasis received 0.1 mg/kg of enalkiren(H-((beta,beta-dimethyl)-beta-Ala)-(4-OCH₃)Phe-His amide of2(S)-amino-1cyclohexyl-3(R), 4(S)-dihydroxy-6-methylheptane diaceticacid salt)(enalkiren 5.0 mg/5 ml (0.1% concentration), glacial aceticacid 0.91 mg/5ml and sodium chloride 43.9 mg/5 ml in water forinjection) intravenously over a 5 minute period, followed 40 minuteslater by administration of an additional 0.3 mg/kg of enalkirenintravenously over a 5 minute period. The psoriatic lesions on thepatient's elbow, face and scalp were graded prior to treatment and 2, 4and 7 days following treatment. The results are shown in Table 1.

                  TABLE 1                                                         ______________________________________                                        Lesion Ranking Following Treatment with Enalkiren                                     Treatment                                                                     Day     +2 Days   +4 Days  +7 Days                                    ______________________________________                                        Right Elbow                                                                   Lesions                                                                       scaling   4         4         3      3                                        erythema  4         4         3      3                                        lesion severity                                                                         4         4         3      3                                        Face Lesions                                                                  erythema  3         3         2      2                                        Scalp Lesions                                                                 erythema  4         4         3      3                                        ______________________________________                                        Grading Scale:                                                                Scaling                                                                       0         None                                                                1         Minimal: poorly defines scales, possibly dusty                                appearance                                                          2         Moderate: defined scales, flat surface edges                        3         Severe: well defined, raised and lifted scales,                               possible yellow/brown color                                         4         Extreme: scales totally cover plaque, raised                                  edges, may be pigmented, possible "crusty"                                    fissures may be present                                             Erythema                                                                      0         None                                                                1         Very Mild: light red/pink                                           2         Moderate: red but still not dark in texture                         3         Strong: very red, possibly dark                                     4         Extreme: angry red                                                  Lesion Severity                                                               0         Complete clearing                                                   1         Minimal severity                                                    2         Moderately severe                                                   3         Severe                                                              4         More severe                                                         ______________________________________                                    

The data provided in Table 1 indicates that the renin inhibitor causedan improvement in the patient's psoriasis.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, adipate, alginate, citrate,aspartate, benzoate, benzenesulfonate, bisulfate, butyrate, camphorate,camphorsulfonate, digluconate, cyclopentanepropionate, dodecylsulfate,ethanesulfate, glucoheptonate, glycerophosphate, hemisulfate, heptonate,hexanoate, fumarate, hydrochloride, hydrobromide, hydroiodide,2-hydroxy-ethanesulfate, lactate, maleate, methanesulfonate, nicotinate,2-naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate,3-phenylpropionate, picrate, pivalate, propionate, succinate, tartrate,thiocyanate, tosylate, and undecanoate. Also, the basicnitrogen-containing groups can be quarternized with such agents asloweralkyl halides, such as methyl, ethyl, propyl, and butyl chloride,bromides, and iodides; dialkyl sulfates like dimethyl, diethyl, dibutyl,and diamyl sulfates, long chain halides such as decyl, lauryl, myristyland stearyl chlorides, bromides and iodides, aralkyl halides like benzyland phenethyl bromides and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

Example of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acids, sulphuric acid, and phosphoric acid and such organicacids as oxalic acid, maleic acid, fumaric acid, succinic acid andcitric acid. Other salts include salts with alkali metal or alkalineearth metals, such as sodium, potassium, calcium or magnesium or withorganic bases.

The compounds of the present invention can also be used in the form ofprodrugs which include esters. Examples of such esters include ahydroxyl-substituted compound of the invention which has been acylatedwith a blocked or unblocked amino acid residue, a phosphate function, ora hemisuccinate residue. The amino acid esters or particular interestare glycine and lysine; however, other amino acid residues can also beused. Other esters include the compounds of the invention wherein acarboxylic acid group has been esterfied to provide esters whichinclude, but are not limited to, methyl, ethyl or benzyl esters. Theseesters serve as prodrugs of the compounds of the present invention. Theprodrugs are metabolically converted in vivo to parent compound. Thepreparation of the pro-drug esters is carried out by reacting ahydroxy-substituted renin inhibitor with an activated amino acyl,phosphoryl or hemisuccinyl derivative. The resulting product is thendeprotected to provide the desired pro-drug ester. Prodrugs which areesters of carboxylic acid group containing renin inhibitors are preparedby methods known in the art.

The novel method of this invention is directed to the use of a renininhibitor for treatment of psoriasis in a human or other mammal.

This invention is also directed to renin inhibitor compositions usefulfor treating psoriasis.

Total daily dose administered to a host in single or divided doses maybe in amounts, for example, from 0.001 to 10 mg/kg body weight daily andmore usually 0.01 to 1 mg/kg. Dosage unit compositions may containingsuch amounts of submultiples thereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

The renin inhibitor may be administered orally, parenterally, byinhalation spray, by nasal spray, rectally, or topically in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired.

Topical compositions comprising the renin inhibitor can be in the formof shampoos, salves, powders, sprays, ointments, lotions, creams,solutions, suspensions and the like. These topical compositions can beprepared by mixing the renin inhibitor with non-toxic, inert solid orliquid carriers which are suitable for topical administration. Topicaladministration may also involve the use of transdermal administrationsuch as transdermal patches of iontophoresis devices.

The term parenteral as used herein includes subcutaneous injections,intravenous injection, intramuscular injection, intrasternal injection,intradermal injection, intralesional injection, or infusion techniques.Injectable preparations, for example, sterile injectable aqueous oraleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-butanediol. Among the acceptablevehicles and solvents that may be employed are water, dextrose solution,mannitol solution, Ringer's solution, and isotonic sodium chloridesolution. In addition, sterile, fixed oils are conventionally employedas a solvent or suspending medium. For this purpose any bland fixed oilmay be employed including synthetic mono- or diglycerides. In addition,fatty acids such as oleic acid find use in the preparation ofinjectables. Injectable preparations can be in ready to use form orreconstituted from a lyophilized powder.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsuled,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.Solid dosage forms can also comprise agents for enhancing oralabsorption. Solid dosage forms can also comprise liquid filled capsules,for example PEG solutions of the active compound in a soft elasticgelatin capsule.

A typical tablet dosage form comprises the active ingredient (no morethan 35% by weight of the tablet), citric acid (5-15% by weight of thetablet), a filler such as microcrystalline cellulose (for example,Avicel® PH101), a disintegrant (8-12% by weight of the tablet, forexample, crospovidone) and a lubricant (0.5-1.5% by weight of thetablet, for example, magnesium stearate. A tablet can also comprise oneor more surfactants (for example, Tween 80, Brij®35, Emulphor 719 andthe like), with the total amount of surfactants being 2-3% by weight ofthe tablet.

The tablet dosage form is prepared by blending the active ingredient,50% of the citric acid and the Avicel®. Ethanol (200 proof) is added andthe mixture is granulated. If surfactants are included, they are addedas a solution in the ethanol during the granulation step. The granulesare dried overnight and screened through a 14 mesh screen. The remaining50% of the citric acid, the crospovidone and the magnesium stearate areblended with the granules and then compressed into tablets. Thecomposition of two typical tablet dosage forms (100 mg of activeingredient) is shown below.

                  TABLE                                                           ______________________________________                                        Composition A                                                                                   Amount Per Tablet                                           Ingredient          mg     %                                                  ______________________________________                                        Compound of Example 3                                                                             107.2  30.6                                               hydrochloride salt                                                            citric Acid          50.1  14.3                                               Avicel ® PH101  150.0  42.8                                               crospovidone         40.0  11.4                                               magnesium stearate   3.0    0.9                                               ______________________________________                                    

    ______________________________________                                        Tablet Composition B                                                                            Amount Per Tablet                                           Ingredient          mg      %                                                 ______________________________________                                        Compound of Example 3                                                                             107.2   30.3                                              hydrochloride salt                                                            citric acid         49.9    14.1                                              Avicel ® PH101  150.7   42.6                                              Brij ® 35       2.5     0.7                                               Tween 80            0.7     0.2                                               crospovidone        40.0    11.3                                              magnesium stearate  2.8     0.8                                               ______________________________________                                    

A typical capsule dosage form comprises a soft elastic gelatin capsulefilled with a solution comprising the active ingredient dissolved in asolvent comprising a mixture of PEG 400 (98% volume/volume) and glycerin(2% volume/volume).

A typical soft elastic gelatin capsule has a composition comprisinggelatin NF (38.3% by weight), glycerin (96% active; 29.0% by weight) andwater (32.7%).

The capsule dosage form is prepared by mixing appropriate volumes of PEG400 and glycerin to give a mixture which is 98% by volume PEG 400 and 2%by volume glycerin. Nitrogen is bubbled through the mixture for severalhours. While maintaining the mixture under a nitrogen atmosphere, themixture is heated to about 40 C. and then the desired amount of theactive ingredient is dissolved. The solution of active ingredient isthen filled into soft elastic gelatin capsules. The filling operation isconducted under a nitrogen atmosphere.

Using the method described above, soft elastic gelatin capsules can beprepared which contain 0.1 ml of a PEG 400/glycerin (98%/2% by volume)solution of the compound of Example 3 (hydrochloride) at concentrationsof 0.7 mg/ml, 7 mg/ml and 21 mg/ml.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

In addition to being used as the sole active ingredient for treatingpsoriasis, a renin inhibitor can be administered in combination with oneor more other agents known to be useful for treating psoriasis. Suchother agents include anthralin (dihydroxyanthralin), azarabine,colchicine, fluorouracil, methotrexate, methoxsalen (8-methoxypsoralen),resorcinol, retinoids (for example, reinoic acid), corticosteroids (forexample, clobetasol propionate, triamcinolone acetonide and the like),cyclosporin, lipoxygenase inhibitors, cyclooxygenase inhibitors,leukotriene synthesis inhibitors, iodochhlorhydroxyquin, salicylic acid,vitamin D, dapsone, somatostatin, sulfur, tars, zinc oxide, ultra-violetlight treatment (UVA or UVB) and PUVA treatment. The renin inhibitor andthe other agent for treating psoriasis can be administered as part ofthe same compositions or as separate compositions.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds, method andcompositions. Variations and changes which are obvious to one skilled inthe art are intended to be within the scope and nature of the inventionwhich are defined in the appended claims.

What is claimed is:
 1. A method for treating psoriasis comprisingadministering to a human or other mammal in need thereof atherapeutically effective amount of a renin inhibitor.
 2. The methodclaim 1 wherein the renin inhibitor is a compound of the formula:##STR45## wherein A_(f) is hydrogen, loweralkyl, arylalkyl, --OR_(10f)or --SR_(10f) wherein R_(10f) is hydrogen, loweralkyl or aminoalkyl,--NR_(11f) R_(12f) wherein R_(11f) and R_(12f) are independentlyselected from hydrogen, loweralkyl, aminoalkyl, cyanoalkyl,hydroxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, (amino)carboxyalkyl,((N-protected)amino)carboxyalkyl, (alkylamino)carboxyalkyl,((N-protected)alkylamino)carboxyalkyl, (dialkylamino)carboxyalkyl,(amino)alkoxycarbonylalkyl, ((N-protected)amino)alkoxycarbonylalkyl,(alkylamino)alkoxycarbonylalkyl,((N-protected)alkylamino)alkoxycarbonylalkyl and(dialkylamino)alkoxycarbonylalkyl; orA_(f) is ##STR46## wherein B_(f) isNH, alkylamino, S, O, CH₂ or CHOH and R_(23f) is loweralkyl, cycloalkyl,aryl, arylalkyl, alkoxy, alkenyloxy, hydroxyalkoxy, dihydroxyalkoxy,arylalkoxy, arylalkoxyalkyl, amino, alkylamino, dialkylamino,(Hydroxyalkyl)(alkyl)amino, (dihydroxyalkyl)(alkyl)amino, aminoalkyl,N-protectedaminalkyl, alkylaminoalkyl, (N-protected)(alkyl)aminoalkyl,dialkylaminoalkyl, carboxyalkoxyalkyl, (alkoxycarbonyl)alkoxyalkyl,carboxyalkyl, carboxyalkylamino, alkoxycarbonyalkyl,alkoxycarbonyalkylamino, (amino)carboxyalkyl, (amino)carboxyalkylamino,((N-protected)amino)carboxyalkyl, ((N-protected)amino)carboxyalkylamino,(alkylamino)carboxyalkyl, (alkylamino)carboxyalkylamino,((N-protected)alkylamino)carboxyalkyl,((N-protected)alkylamino)carboxyalkylamino, (dialkylamino)carboxyalkyl,(dialkylamino)carboxyalkylamino, (amino)alkoxycarbonylalkyl,(amino)alkoxycarbonylalkylamino, ((N-protected)amino)alkoxycarbonyalkyl,((N-protected)amino)alkoxycarbonylalkylamino,(alkylamino)alkoxycarbonylalkyl,(alkylamino)alkoxycarbonylalkylamino,((N-protected)alkylamino)-alkoxycarbonylalkyl,((N-protected)alkylamino)alkoxycarbonyl-alkylamino,(dialkylamino)alkoxycarbonylalkyl,(dialkylamino)alkoxycarbonylalkylamino,aminocycloalkyl, aminoalkylamino, dialkylaminoalkyl(alkyl)amino,arylalkylamino, arylalkyl(alkyl)amino, alkoxyalkyl(alkyl)amino,(polyalkoxy)alkyl(alkyl)amino, di-(alkoxyalkyl)amino,di-(hydroxyalkyl)amino, di-((polyalkoxy)alkyl)amino, polyalkoxy,(polyalkoxy)alkyl, (heterocyclic)alkyl or a substituted or unsubstitutedheterocyclic wherein saturated heterocyclics may be unsubstituted,monosubstituted or disubstituted with hydroxy, oxo, amino, alkylamino,dialkylamino, alkoxy, polyalkoxy or loweralkyl; unsaturated heterocylicsmay be unsubstituted or monosubstituted with hydroxy, amino, alkylamino,dialkylamino, alkoxy, polyalkoxy or loweralkyl; W_(f) is C═O or CHOH;U_(f) is CH₂ or NR_(2f) provided that when W_(f) is CHOH then U_(f) isCH₂ ; R_(1f) is loweralkyl, cycloalkylmethyl, benzyl, 4-methoxybenzyl,halobenzyl, (1-naphthyl)methyl, (2-naphthyl)methyl,(4-imidazolyl)methyl, (alpha,alpha)-dimethylbenzyl, 1-benzyloxyethyl,phenethyl, phenoxy, thiophenoxy or anilino; provided that when R_(1f) isphenoxy, thiophenoxy or anilino, then B_(f) is CH₂ or CHOH or A_(f) ishydrogen; R_(2f) is hydrogen or loweralkyl; R_(3f) is loweralkyl,loweralkenyl, ((alkoxy)alkoxy)loweralkyl, (thialkoxy)alkyl, benzyl orheterocyclic rig substituted methyl; R_(6f) is loweralkyl,cycloalkylmethyl or benzyl; R_(af) is vinyl, formyl, hydroxymethyl orhydrogen; R_(df) is hydrogen or loweralkyl; R_(bf) and R_(ef) areindependently selected from OH and NH₂ ; and R_(cf) is hydrogen,loweralkyl, vinyl or arylalkyl; or a pharmaceutically acceptable salt,ester or prodrug thereof.
 3. The method of claim 1 wherein the renininhibitor is a compound of the formula: ##STR47## wherein A_(i) is(I)R_(5i) C(O)--CH₂)_(2") --wherein1) w" is 0 to 4 and 2) R_(5i) isi)hydroxy, ii) alkoxy, iii) thioalkoxy, iv) amino or v) substituted amino;(II) alkylsulfonyl, (aryl)sulfonyl or (heterocyclic)sulfonyl; (III)aryl, arylalkyl, heterocyclic or (heterocyclic)alkyl; or (IV) R_(90i) --or R_(90i) NHC(O)-- wherein R_(90i) is a C₁ to C₄ straight or branchedcarbon chain substituted by a substituent selected from1) carboxy, 2)akoxycarbonyl, 3) alkylsulfonyl, 4) aryl, 5) arylsulfonyl, 6)heterocylic or 7) (heterocyclic)sulfonyl); R_(1i) is (I) hydrogen (II)loweralkyl, (III) loweralkenyl, (IV) cycloalkylalkyl, (V)cycloalkenylalkyl, (VI) aryloxyalkyl, (VII) thioaryloxyalkyl, (IV)arylalkoxyalkyl, (IX) arylthioalkoxyalkyl or (X) a C₁ to C₃ straight orbranched carbon chain substituted by a substituent selected from1)alkoxy 2) thioalkoxy, 3) aryl and 4) heterocyclic; X_(i) is (I) CH₂,(II) CHOH, (III) C(O), (IV) O, (VI) S, (VII) S(O), (VIII) SO₂, (IX) N(O)or (X) --P(O)--; R_(3i) is (I) loweralkyl, (II) haloalkyl, (III)loweralkenyl, (IV) cycloalkylalkyl, (V) cycloalkenyalkyl, (VI)alkoxyalkyl, (VII) thioalkoxyalkyl, (IX) hydroxyalkyl, (X) --CH₂)_(ee)NHR_(12i) wherein1) ee is 1 to 3 and 2) R_(12i) isi) hydrogen, ii)loweralkyl or iii) an N-protecting group; (XI) arylalkyl or (XII)(heterocyclic)alkyl; and T_(i) is ##STR48## wherein R_(4i) is (I)loweralkyl, (II) cycloalkylalkyl (III) cycloalkenyalkyl or (IV)arylalkyl; and D_(i) is (I) ##STR49## wherein R_(73i) is loweralkyl,(II) ##STR50## wherein 1) M_(i) isi) O, ii) S or iii) NH; 2) Q_(i) isi)O or ii) S; 3) E_(i) isi) O, ii) S, iii) CHR_(73i) wherein R_(73i) isloweralkyl, iv) C═CH₂ or v) NR_(18i) wherein R_(18i) isa) hydrogen, b)loweralkyl, c) hydroxyalkyl, d) hydroxy, e) alkoxy, f) amino or g)alkylamino; and 4) G_(i) si) absent, ii) CH₂ or iii) NR_(19i) whereinR_(19i) is hydrogen or loweralkyl, with the proviso that when G_(i) isNR_(19i') then R_(18i) is loweralkyl or hydroxyalkyl; (III) ##STR51##wherein 1) v" is 0 or 1 and2) R_(21i) isi) NH, ii) O, iii) S or iv) SO₂; or (IV) a substituted methylene group; or a pharmaceuticallyacceptable salt ester or prodrug thereof.
 4. The method of claim 1wherein the renin inhibitor is enalkiren.
 5. The method of claim 1wherein the renin inhibitor is 2(S)-(1(S)-(4-(Methoxymethoxy)piperidin-1-yl)carbonyl-2-phenyl)ethoxyhexanoic acid amide of3-(4-morpholinyl)propyl-5-(S)-amino-6-cyclohexyl-4(S)-hydroxy-2(S)-isopropylhexanamide;or a pharmaceutically acceptable salt, ester or prodrug thereof.
 6. Themethod of claim 1 wherein the renin inhibitor is2(S)-2-Benzyl-3-(1-methylpiperazin-4-ylsulfonyl)-propionyl-(L)-(4-thiazolyl)alanyl amide of(2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane; or apharmaceutically acceptable salt, ester or prodrug thereof.
 7. Themethod of claim 1 wherein the renin inhibitor isN-(4-Morpholinylsulfonyl)-(L)-Phenylalanyl-(L)-(2-amino-4-thiazolyl)Alanylamide of (2S,3R,4S)-2-amino-1-cyclohexyl-3,4-dihydroxy-6-methylheptane;or a pharmaceutically acceptable salt, ester or prodrug thereof.
 8. Themethod of claim 1 wherein the renin inhibitor is administered topically.9. A method for treating psoriasis comprising administering to a humanor other mammal in need thereof a therapeutically effect amount of arenin inhibitor in combination with a therapeutically effective amountof another agent which is useful for treating psoriasis.